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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 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.

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 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.

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.

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

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.

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.

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.

Purpose: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME).Design: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis.Participants: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography.Methods: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months.Main Outcome Measures: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP).Results: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (−111.6 μm) and DEX implant 0.35 mg (−107.9 μm) than sham (−41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.Conclusions: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.

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.

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.

Purpose To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. Design Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. Methods setting: Forty-eight clinical sites. patients: Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. intervention procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. main outcome measures: The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. Results A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (n = 250), AL-8309B 1.75% (n = 258), or vehicle (n = 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76, and 1.71 mm 2 for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. Conclusions AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons.

BACKGROUND AND OBJECTIVE: To investigate the clinical course and outcomes of patients with vitreomacular traction (VMT) managed initially by observation. PATIENTS AND METHODS: This noncomparative case series included patients with a diagnosis of VMT based on clinical symptoms and findings on spectral-domain optical coherence tomography (SD-OCT) between 2005 and 2014. VMT was documented using a standardized grading system based on the degree of distortion of the foveal contour. Data were collected at five retina clinics using standardized collection forms. Visual acuity, changes in SD-OCT findings, and timing of the release of VMT as seen on SD-OCT were recorded. RESULTS: The study included 230 eyes of 185 patients. Mean age was 72.5 years, and mean follow-up was 32 months. At baseline, VMT grading was grade 1 in 92 eyes (40%), grade 2 in 118 eyes (51.3%), and grade 3 in 20 eyes (8.7%). By last follow-up, spontaneous release of VMT occurred in 73 eyes (31.7%). Spontaneous release of VMT occurred at a mean of 18 months (median: 10.9 months) after initial visit. Mean logMAR best corrected visual acuity (BCVA) was 0.28 (20/55) (range: 20/20 to 20/400) at baseline and 0.25 (20/51) (range: 20/20 to 20/400) at last follow-up. Pars plana vitrectomy was performed in 10 eyes (4.1%) for macular hole (six eyes) and increased VMT (four eyes); BCVA was at least 20/40 in eight of the 10 eyes at last follow-up. CONCLUSION: Patients with VMT generally had a favorable clinical course when managed initially by observation. Spontaneous release of VMT occurred in approximately one-third of patients. At last follow-up, pars plana vitrectomy was performed in fewer than 5% of patients. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:571–576.]

Purpose To evaluate clinical outcomes and safety up to 12 months after ocriplasmin injection for the treatment of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT) in a real-world setting. Design The Phase IV Ocriplasmin Research to Better Inform Treatment (ORBIT) trial ( NCT02079883 ) was a Phase IV multicenter, prospective, observational study. Participants Patients aged ≥18 years with symptomatic VMA/VMT treated with ocriplasmin. Methods Patients received a single 0.125 mg intravitreal injection of ocriplasmin. All assessments and treatment decisions were at the discretion of the treating physician. Spectral-domain OCT (SD-OCT) images were analyzed by an independent central reading center (CRC). All enrolled patients were included in demographic, baseline characteristics, and safety analyses. Patients with symptomatic VMA/VMT at baseline determined by CRC were included in baseline ocular characteristics and efficacy analyses. Main Outcome Measures Clinical outcomes were measured up to 12 months and included resolution of symptomatic VMA, closure of full-thickness macular hole (FTMH), mean change from baseline in best-corrected visual acuity (BCVA), incidence of vitrectomy, and time to first vitrectomy. Safety outcomes included the incidence and timing of onset of adverse drug reactions (ADRs). Results Of the 539 patients enrolled, 480 were determined to have symptomatic VMA/VMT at baseline post-CRC assessment. After treatment with ocriplasmin, the rate of VMA/VMT resolution was 45.8% (95% confidence interval [CI], 41.3–50.4) at month 1 and 59% (95% CI, 54.4–63.4) at months 10 to 12. The rate of FTMH closure was 30.5% (95% CI, 22.4–39.7) at month 1 and 32.2% (95% CI, 23.9–41.4) at months 10 to 12. Mean (standard deviation) change from baseline in BCVA was 1.5 (11.19) letters at month 1 and 5.2 (13.60) letters at months 10 to 12. Vitrectomy was performed in 28.5% of patients, with a median time to vitrectomy of 63 days. Adverse drug reactions were reported by 30.6% of patients; 5.2% experienced a serious ADR. Conclusions Results from the ORBIT study demonstrate that treatment with ocriplasmin is effective and well tolerated in patients with symptomatic VMA/VMT in a real-world setting. The percentage of patients with VMA/VMT resolution at month 1 was higher than previously reported in well-controlled clinical trials. No new safety signals were identified.

Purpose To assess the long-term comparative effectiveness of ranibizumab versus switching to aflibercept in neovascular age-related macular degeneration (nAMD). Design A 24-month, retrospective, comparative, nonrandomized, matched cohort study. Participants Patients with nAMD initiated on ranibizumab who remained (nonswitchers) or who switched to aflibercept (switchers) captured from a United States electronic medical records database between July 1, 2011 and October 12, 2014. Methods Patient eyes were matched for baseline age, baseline visual acuity (VA), VA at month 3, and duration of follow-up. Matching ratio was 1:2 (switchers: nonswitchers) where possible and 1:1 otherwise. Main Outcome Measures The primary outcome was VA change from baseline (first injection of ranibizumab) to month 24. Secondary end points were standardized area under the curve of VA change; patient eyes (%) gaining or losing ≥5, ≥10, or ≥15 letters, or with VA of >73 letters at month 24; number of injections and monitoring visits; and analysis of preswitch characteristics. Results A total of 454 switchers and 750 matched nonswitchers were included. The adjusted difference in mean VA change from baseline to month 24 for switchers to nonswitchers was 0.02 letters (95% confidence interval [CI], –1.63 to 1.68). The upper bound 95% CI (1.68) was below the predefined noninferiority margin of 5 letters. Switchers had a significantly higher annualized number of mean total visits compared with nonswitchers (10.0 vs. 9.0 for year 1; 8.7 vs. 7.4 for year 2), a higher number of injection visits (8.4 vs. 6.7 for year 1; 7.0 vs. 5.1 for year 2), but a lower number of monitoring-only visits (1.6 vs. 2.3 for year 1; 1.7 vs. 2.3 for year 2). During the preswitch period, switchers had a higher number of injection visits (7.6 vs. 6.5), fewer monitoring-only visits (1.5 vs. 2.2), and comparable total visits (9.1 vs. 8.7). Visual acuity change from baseline to switch was similar between switchers and nonswitchers (adjusted least squares mean difference, –1.36 letters; 95% CI, –2.76 to 0.05). Conclusions Switching patients from ranibizumab to aflibercept resulted in no difference in VA change compared with those maintained on ranibizumab only. The lower retreatment rate in nonswitchers compared with switchers post switch does not support the view of a longer treatment efficacy.

Background/aimsTo evaluate the efficacy and safety of individualised 2.0 mg intravitreal aflibercept retreatment for diabetic macular oedema (DME) through the fifth year of management.MethodsThis is a phase IV, 2-year, open-label extension study. Sixty patients completing the 3-year VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial enrolled in the ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study. All patients received aflibercept in the presence of clinically relevant DME. Intervals between visits were prescribed according to disease activity. The main outcome measure was mean aflibercept injections given through 2 years.ResultsA mean of 7.7 aflibercept injections were administered through 2 years. Fifteen (25%) patients required no retreatment and 48% (n=29) of patients received five or fewer injections through 2 years. Among patients who received at least one aflibercept retreatment during ENDURANCE, the mean number of injections through 2 years was 9.5. The mean visual acuity and central retinal thickness gains achieved during VISTA DME were maintained and stable during ENDURANCE. The most notable safety signal was progression of diabetic retinopathy. Six (10%) patients converted from non-proliferative to proliferative diabetic retinopathy (PDR), and a total of eight patients experienced PDR events occurring at a mean of 387 days following the previous aflibercept treatment.ConclusionThe need for aflibercept retreatment was substantially reduced in the fourth and fifth years of aflibercept dosing for DME following initiation of therapy in the VISTA DME trial. While vision gains achieved during the 3-year VISTA DME trial were maintained through ENDURANCE with a reduced treatment burden, clinically relevant worsening of diabetic retinopathy was observed with progression to PDR in 10% of the eyes.Trial registration numberNCT02299336

Importance An oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor. Objective To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD. Design, Setting, and Participants Phase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive. Interventions Participants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography. Main Outcomes and Measures The main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections. Results Of the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by −50 [97] μm, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1). Conclusions and Relevance X-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17% of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way.

To investigate the relationship between ganglion cell complex (GCC) thickness and photoreceptor alterations in eyes with intermediate age-related macular degeneration (AMD).Retrospective case-control study.We collected data from 68 eyes with intermediate AMD from 68 patients with spectral-domain optical coherence tomography (SDOCT) imaging. A control group of 50 eyes from 50 healthy subjects was included for comparison. Our main outcome measures for comparison between groups were (1) the average and minimum GCC thickness and (2) the "normalized" reflectivity of the ellipsoid zone (EZ) en face image.The average and minimum GCC thicknesses were thinner in AMD patients (69.54 ± 9.30 μm and 63.22 ± 14.11 μm, respectively) than in healthy controls (78.57 ± 6.28 μm and 76.28 ± 6.85 μm, P.0001 and P.0001, respectively). Agreement was found to be excellent in the "normalized" EZ reflectivity assessment (intraclass correlation coefficient = 0.986, coefficient of variation = 1.11). The EZ "normalized" reflectivity was 0.67 ± 0.11 in controls and 0.61 ± 0.09 in the AMD group (P = .006). In univariate analysis, EZ "normalized" reflectivity was found to have a significant direct relationship with average (P.0001) and minimum (P.0001) GCC thickness in AMD patients, but not in controls (P = .852 and P = .892, respectively).Eyes with intermediate AMD exhibit GCC thinning, as well as a reduced EZ "normalized" reflectivity, and these parameters are correlated. This study supports the concept of postreceptor retinal neuronal loss as a contributor to retinal thinning in intermediate AMD.

The advent of anti-vascular endothelial growth factor treatment has changed the prognosis for patients with neovascular age-related macular degeneration (nvAMD). The ability to stabilize or improve vision with these treatments is a major step in enabling patients to continue to function at the highest possible level. Many studies have demonstrated that the better the visual acuity (VA) is at the time of treatment initiation, the higher the likelihood that VA will be better during at least the following 2 years; as such, detection of nvAMD when VA is relatively good is important. Data on the VA of patients with intermediate AMD and VA at the time of nvAMD diagnosis suggest that patients are typically losing an average of 3 to 5 lines of vision and possibly more between the time that intermediate AMD progresses to nvAMD and the diagnosis of nvAMD is made. The average patient may have nvAMD for 6 to 12 months before diagnosis and treatment initiation. Current efforts in management of nvAMD are primarily aimed at optimizing anti-vascular endothelial growth factor treatments that have the potential to improve VA outcomes by a magnitude of letters. Additional tools or other efforts to identify patients with nvAMD before substantial vision loss has occurred may reduce the amount of visual loss sustained with anti-vascular endothelial growth factor therapy, and have the potential to improve VA outcomes substantially.

The purpose of the study was to investigate the clinical course of patients with idiopathic vitreomacular adhesion (VMA).A noncomparative case series of patients who had clinical symptoms and spectral-domain optical coherence tomography findings consistent with VMA. The VMA was graded based on the optical coherence tomography findings at initial and follow-up examinations. Grade 1 was incomplete cortical vitreous separation with attachment at the fovea, Grade 2 was the Grade 1 findings and any intraretinal cysts or clefts, and Grade 3 was the Grade 2 findings and the presence of subretinal fluid.One hundred and six eyes of 81 patients were identified as having VMA by spectral-domain optical coherence tomography at 3 retina clinics. The mean age was 73 years and the mean time of follow-up was 23 months. Forty-three eyes (41%) had Grade 1 VMA, 56 eyes (52%) had Grade 2 VMA, and 7 eyes (7%) had Grade 3 VMA. By the last follow-up, spontaneous release of VMA occurred in 34 eyes (32%), and pars plana vitrectomy was performed in 5 eyes (4.7%). Mean best-corrected visual acuity was 0.269 logarithm of the minimum angle of resolution or 20/37 at baseline (range, 20/20-20/200) and logarithm of the minimum angle of resolution 0.251 or 20/35 at the last examination (range, 20/20-20/400).In this selected patient cohort with mild symptoms, the clinical course of patients with VMA managed by initial observation was generally favorable.

The geographic origins of populations can be identified by their maternally inherited mitochondrial DNA (mtDNA) haplogroups. This study compared human cybrids (cytoplasmic hybrids), which are cell lines with identical nuclei but mitochondria from different individuals with mtDNA from either the H haplogroup or L haplogroup backgrounds. The most common European haplogroup is H while individuals of maternal African origin are of the L haplogroup. Despite lower mtDNA copy numbers, L cybrids had higher expression levels for nine mtDNA-encoded respiratory complex genes, decreased ATP (adenosine triphosphate) turnover rates and lower levels of reactive oxygen species production, parameters which are consistent with more efficient oxidative phosphorylation. Surprisingly, GeneChip arrays showed that the L and H cybrids had major differences in expression of genes of the canonical complement system (5 genes), dermatan/chondroitin sulfate biosynthesis (5 genes) and CCR3 (chemokine, CC motif, receptor 3) signaling (9 genes). Quantitative nuclear gene expression studies confirmed that L cybrids had (a) lower expression levels of complement pathway and innate immunity genes and (b) increased levels of inflammation-related signaling genes, which are critical in human diseases. Our data support the hypothesis that mtDNA haplogroups representing populations from different geographic origins may play a role in differential susceptibilities to diseases.

Diabetic macular edema (DME) is the leading cause of vision loss in the working-age population in developed countries. Management has traditionally consisted of focal/grid macular laser, according to the guidelines established by the Early Treatment of Diabetic Retinopathy Study. More recent prospective clinical trials examining the effect of intravitreal ranibizumab in the treatment of DME—most notably, READ-2, RESOLVE, RESTORE, RISE/RIDE, and DRCR.net protocol I—have demonstrated improved visual outcomes with pharmacologic targeting of vascular endothelial growth factor. Similar treatment benefits have also been noted in clinical trials evaluating intravitreal bevacizumab and aflibercept (BOLT and DA VINCI, respectively). Intravitreal steroids, particularly in refractory cases, continue to have a limited role in the management of DME. In patients with symptomatic visual loss, the treatment paradigm for DME has shifted toward intravitreal pharmacotherapeutics, principally anti–vascular endothelial growth factor therapy, and this review examines the clinical trials leading to this change.

Purpose To determine the effectiveness of different monitoring modalities to detect incident neovascularization associated with age-related macular degeneration (AMD). Methods Secondary analyses compared the rates of detecting incident neovascular AMD in prescheduled office visits versus office visits triggered by monitoring device or by symptom realization in a randomized trial evaluating home telemonitoring device plus standard care (device arm) versus standard care alone. Results At prescheduled office visits, neovascular AMD was detected in 14/1927 visits (0.7%, 95% confidence interval [CI]: 0.4%-1.1%) and 14/1949 visits (0.7%, 95% CI: 0.3%-1.1%) in the device and standard care alone arms, respectively. Thirty-seven participants with neovascular AMD were detected in 318 office visits (11.6%, 95% CI: 8.1%-15.2%) triggered by device or symptom realization and 17 neovascular AMD in 65 office visits (26%, 95% CI: 15.5%-36.8%) triggered by symptom realization in the device and standard care alone arms, respectively. The home device strategy had a higher neovascular-AMD detection rate than prescheduled office visits (relative risk = 16.0 [95% CI: 8.8-29.3]). Neovascular AMD detected at triggered visits were associated with less vision loss from baseline in the device arm versus standard care alone arm (-3 letters vs. -11.5 letters, respectively, P = 0.03). Conclusion Telemonitoring may alter the management of patients with AMD and improve vision outcomes.

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).Multicenter, prospective, randomized clinical trial.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).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.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.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, P0.001). There were no cases of endophthalmitis, and the total incidence of Anti-Platelet Trialists' Collaboration events was 4.7%.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.

Purpose Increasing drusen volume was proposed to be a predictor of disease progression in age-related macular degeneration (AMD). In patients with late AMD in one eye, the fellow eyes without neovascularization are known to be at higher risk of developing exudative AMD. We evaluated the relationship between drusen volume in these fellow eyes and their progression to late AMD. Methods A retrospective analysis included fellow eyes with drusen associated with nonexudative AMD. All eyes with neovascular AMD were treated with intravitreal ranibizumab, aflibercept, and/or bevacizumab and followed for 2 years. All eyes were scanned with the Cirrus HD-OCT using a 512 × 128 scan pattern. Optical coherence tomography (OCT) data at baseline, month 12, and month 24 were collected using the advanced RPE analysis tool to quantify drusen volume within 3- and 5-mm-diameter circles centered on the fovea. Optical coherence tomography scans were also evaluated for the development of geographic atrophy (GA) or macular neovascularization (MNV). Results Eighty-nine patients who had neovascular AMD in only one eye were studied. Optical coherence tomography drusen volume in the absence of MNV could be measured in 61 participants (68.5%). After 12 months, 4 eyes (4.5%) developed MNV and 15 eyes (16.9%) developed GA. By 24 months of follow-up, an additional 5 eyes (7.1%) developed MNV and an additional 10 eyes (14.3%) developed GA. At month 24, the eyes that developed GA or MNV had baseline drusen volumes that were significantly larger than in eyes that did not develop late AMD. Patients with a drusen volume over 0.03 mm3 had a greater than 4-fold increased risk for developing late AMD compared with those with lower drusen volumes. Conclusions Baseline drusen volume appears to be an important predictor for the development of late AMD within 2 years in eyes that have fellow eyes being actively treated for MNV. This suggests that OCT-derived drusen volume measurements may be a useful biomarker to identify eyes at the highest risk for progression to late AMD.

Purpose To assess the ocular and systemic safety of intravitreal aflibercept injection (IAI) compared with controls in IAI trials in neovascular age-related macular degeneration (nAMD), macular edema following central retinal vein occlusion (MEfCRVO), macular edema following branch retinal vein occlusion (MEfBRVO), and diabetic macular edema (DME). Design Comprehensive review of 10 phase II and III trials of IAI in retinal diseases. Participants Patients were included from IAI trials in nAMD (CLEAR-IT 2 [52 weeks], VIEW 1 [96 weeks], VIEW 2 [96 weeks], VIEW 1 extension [208 weeks]); MEfCRVO (COPERNICUS [100 weeks], GALILEO [76 weeks]); MEfBRVO (VIBRANT [52 weeks]); and DME (DA VINCI [52 weeks], VIVID [100 weeks], VISTA [100 weeks]). Methods Rates were calculated as events/100 person-years at risk (PYR). When applicable, rate ratios (RRs) and 95% confidence intervals (CIs) were provided. Main Outcome Measures Outcomes included rates for intraocular inflammation, endophthalmitis, serious adverse events (SAEs), wound-healing complications, hypertension (HTN), adjudicated Anti-Platelet Trialists' Collaboration (APTC)–defined arterial thromboembolic events (ATEs) (nonfatal myocardial infarction, nonfatal stroke, and vascular death), and death from all causes. Results More than 4000 patients contributed >7000 PYR. For all outcomes, there were no meaningful differences between evaluated adverse event rates for IAI and controls. Overall intraocular inflammation rates were 2.37 (control) and 2.06 (IAI); overall RR was 0.87 (95% CI, 0.61–1.27). Overall endophthalmitis rates were 0.52 (control) and 0.22 (IAI); overall RR was 0.42 (95% CI, 0.18–1.03). Overall SAE rates were 23.09 (control) and 20.80 (IAI); overall RR was 0.90 (95% CI, 0.80–1.02). Overall rates of wound-healing complications were 0.17 (control) and 0.15 (IAI); overall RR was 0.85 (95% CI, 0.24–3.86). Overall HTN rates were 14.87 (control) and 11.27 (IAI), with an overall RR of 0.76 (95% CI, 0.65–0.89); HTN rates were highest in MEfBRVO and lowest in nAMD. For adjudicated APTC-defined ATEs, rates were 2.04 (control) and 2.19 (IAI), with an RR of 1.07 (95% CI, 0.73–1.61). Overall death rates were 1.16 (control) and 1.49 (IAI); overall RR was 1.28 (95% CI, 0.80–2.15). Conclusions Rates of selected ocular and systemic adverse events with IAI were similar to those of controls and similar across disease states in evaluated IAI trials. Intravitreal aflibercept injection was generally well tolerated in the patients evaluated.

To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME).Randomized, double-masked, multicenter, phase 2 clinical trial.Diabetic patients (n = 221) with center-involved DME.Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation.The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline.As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (P ≤ 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group (P ≤ 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser (P = 0.0031, P = 0.0007, P = 0.1608, and P = 0.0016, respectively, versus laser). Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were -165.4 μm, -227.4 μm, -187.8 μm, and -180.3 μm versus -58.4 μm for laser (P0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated. The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure.Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation for the treatment of DME.

To evaluate the safety and efficacy of Ozurdex (dexamethasone intravitreal implant) 0.7 mg in the treatment of diabetic macular edema in vitrectomized eyes.This was a prospective, multicenter, open-label, 26-week study. Fifty-five patients with treatment-resistant diabetic macular edema and a history of previous pars plana vitrectomy in the study eye received a single intravitreal injection of 0.7-mg dexamethasone intravitreal implant. The primary efficacy outcome measure was the change in central retinal thickness from baseline to Week 26 measured by optical coherence tomography.The mean age of patients was 62 years. The mean duration of diabetic macular edema was 43 months. The mean (95% confidence interval) change from baseline central retinal thickness (403 μm) was -156 μm (-190, -122 μm) at Week 8 (P0.001) and -39 μm (-65, -13 μm) at Week 26 (P = 0.004). The mean (95% CI) increase in best-corrected visual acuity from baseline (54.5 letters) was 6.0 letters (3.9, 8.1 letters) at Week 8 (P0.001) and 3.0 letters (0.1, 6.0 letters) at Week 26 (P = 0.046). At Week 8, 30.4% of patients had gained ≥10 letters in best-corrected visual acuity. Conjunctival hemorrhage, conjunctival hyperemia, eye pain, and increased intraocular pressure were the most common adverse events.Treatment with dexamethasone intravitreal implant led to statistically and clinically significant improvements in both vision and vascular leakage from diabetic macular edema in difficult-to-treat vitrectomized eyes and had an acceptable safety profile.

Purpose: To report a patient with known metastatic leiomyosarcoma and a new choroidal mass wherein a fine-needle aspirate biopsy was performed to achieve diagnostic and treatment certainty. Methods: A retrospective case report of one patient. Results: A 63-year-old woman with known metastatic leiomyosarcoma presented with a new choroidal mass. Metastatic leiomyosarcoma to the choroid has been previously reported. An ab externo fine-needle aspirate biopsy was performed to achieve diagnostic and therapeutic certainty (metastatic leiomyosarcoma is considered radiation insensitive and requires local excision, and choroidal melanoma is treated with I135 plaque brachytherapy). The results were positive for choroidal melanoma as read by two different pathologists at two different sites, and the patient was treated in the conventional manner. The response to treatment at 30 months has been excellent. Conclusion: When there is diagnostic uncertainty and treatment regimens vary, a fine-needle aspirate biopsy can be diagnostic and can provide direction for care. De novo tumors can be confounded with a metastatic disease in patients with complex histories.

Objective To evaluate the safety and efficacy of intravitreal ranibizumab in a large population of subjects with neovascular age-related macular degeneration (AMD). Design Twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial. Participants A total of 4300 subjects with angiographically determined subfoveal choroidal neovascularization (CNV) secondary to AMD. Methods Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses. Dose groups were stratified by AMD treatment history (treatment-naive vs. previously treated). Cohort 1 subjects were retreated on the basis of optical coherence tomography (OCT) or visual acuity (VA) criteria. Cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. Main Outcome Measures Safety outcomes included the incidence of ocular and nonocular adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included changes in best-corrected VA over time. Results Some 81.7% of cohort 1 subjects and 49.9% of cohort 2 subjects completed the 12-month study. The average total number of ranibizumab injections was 4.9 for cohort 1 and 3.6 for cohort 2. The incidence of vascular and nonvascular deaths during the 12-month study was 0.9% and 0.7% in the cohort 1 0.3 mg group, 0.8% and 1.5% in the cohort 1 0.5 mg group, and 0.7% and 0.9% in cohort 2, respectively. The incidence of death due to unknown cause was 0.1% in both cohort 1 dose groups and cohort 2. The number of vascular deaths and deaths due to unknown cause did not differ across cohorts or dose groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the 0.3 mg and 0.5 mg groups and cohort 2, respectively. At month 12, cohort 1 treatment-naive subjects had gained an average of 0.5 (0.3 mg) and 2.3 (0.5 mg) VA letters and previously treated subjects had gained 1.7 (0.3 mg) and 2.3 (0.5 mg) VA letters. Conclusions Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA. Future investigations will seek to establish optimal dosing regimens for persons with neovascular AMD. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.