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

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

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

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

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of 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, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly 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 end point 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, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. 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 1 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 [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME) over 3 years. DESIGN: Two similarly designed phase 3 trials: VISTADME and VIVIDDME. PARTICIPANTS: Patients (eyes; n = 872) with central-involved DME. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. From week 24, if rescue treatment criteria were met, IAI patients received active laser, and laser control patients received IAI 2q8. From week 100, laser control patients who had not received IAI rescue treatment received IAI as needed per retreatment criteria. MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at week 52. We report the 148-week results. RESULTS: Mean BCVA gain from baseline to week 148 with IAI 2q4, IAI 2q8, and laser control was 10.4, 10.5, and 1.4 letters (P < 0.0001) in VISTA and 10.3, 11.7, and 1.6 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 148 was 42.9%, 35.8%, and 13.6% (P < 0.0001) in VISTA and 41.2%, 42.2%, and 18.9% (P < 0.0001) in VIVID, respectively. Greater proportions of eyes treated with IAI 2q4 and IAI 2q8 versus those treated with laser control had an improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score in both VISTA (29.9% and 34.4% vs. 20.1% [P = 0.0350, IAI 2q4; P = 0.0052, IAI 2q8]) and VIVID (44.3% and 47.8% vs. 17.4% [P < 0.0001 for both]). In an integrated safety analysis, the most frequent ocular serious adverse event was cataract (3.1%, 2.1%, 0.3% for 2q4, 2q8, and control). CONCLUSIONS: Visual improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148, with similar overall efficacy in the IAI 2q4 and IAI 2q8 groups. Treatment with IAI also had positive effects on the DRSS score. Over 148 weeks, the incidence of adverse events was consistent with the known safety profile of IAI.

Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. METHODS: Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. MAIN OUTCOME MEASURES: Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. RESULTS: At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 µm, 55.4 µm, and 33.3 µm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). CONCLUSIONS: A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN: Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES: The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS: Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS: In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

Stereotactic radiotherapy for polypoidal choroidal vasculopathy: a pilot study.

PURPOSE: To evaluate low-voltage X-ray stereotactic radiotherapy (SRT) delivered in conjunction with intravitreal ranibizumab for the treatment of active macular polypoidal choroidal vasculopathy (PCV). METHODS: At baseline, all eyes received an intravitreal injection of ranibizumab, followed by 16-Gy X-ray SRT to the macula. Further ranibizumab injections were given pro re nata. The primary outcome measure was regression of the polyps assessed by indocyanine green angiography. Secondary outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness (CFT) changes on optical coherence tomography. Local or systemic adverse events were evaluated as well. RESULTS: We examined 12 eyes of 12 patients with PCV. At month 12, an angiographic regression of the polyps was observed in 10 of the 12 eyes. The mean BCVA improved by 7.6 letters: from 65.08 ± 11.4 to 72.7 ± 14.75 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The mean CFT decreased from 372.3 ± 79.6 to 215.9 ± 57.9 µm (p < 0.01). No local or systemic adverse events were reported. CONCLUSIONS: The preliminary data support the safety of low-voltage X-ray SRT for the treatment of macular PCV and show polyp closure, reduction in CFT and improvement in the mean BCVA. Additional research is warranted to confirm the efficacy and longer-term safety of this therapy in this population.

Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47-0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.

Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.

PURPOSE: To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. DESIGN: Two randomized, double-masked, active-controlled, phase 3 trials. PARTICIPANTS: Two thousand four hundred fifty-seven patients with neovascular AMD. METHODS: From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES: Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. RESULTS: Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of -0.64 [95% CI, -0.89 to -0.40] and -0.55 [95% CI, -0.79 to -0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week 96. CONCLUSIONS: All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.

Intravitreal aflibercept for diabetic macular edema.

PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 µm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 µm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

Intraocular pressure in patients with neovascular age-related macular degeneration switched to aflibercept injection after previous anti-vascular endothelial growth factor treatments.

PURPOSE: To assess for change in intraocular pressure (IOP) in neovascular age-related macular degeneration patients switched to aflibercept after receiving previous treatments of intravitreal bevacizumab or ranibizumab. METHODS: This is a retrospective chart review of the first 53 patients (53 eyes) treated with at least 2 injections of 2 mg in 0.05 mL of aflibercept by March 6, 2013, after at least 2 previous injections of 0.5 mg in 0.05 mL of ranibizumab with or without previous injections of 1.25 mg in 0.05 mL of bevacizumab. The analysis was restricted to the first such sequence within each patient. The last previous anti-vascular endothelial growth factor injection before the switch to aflibercept was ranibizumab in all cases included in the study. Each person served as his or her own control. The pre-aflibercept IOP in the before state (treatment with bevacizumab or ranibizumab) was the preinjection IOP measure before dilation at the visit of the first aflibercept injection. Statistical analysis was performed using Microsoft Excel. RESULTS: There were 41 patients who were first treated with ranibizumab followed by aflibercept and 12 patients treated with ranibizumab and bevacizumab followed by aflibercept. For each of these sequences, IOP in the treated eye during treatment with aflibercept (the after state) was computed in 3 different ways: the first IOP, the last IOP, and the mean IOP for the period when treated with aflibercept. The pooled data showed a mean pre-aflibercept (the before state) IOP of 14.87 that decreased to a mean first IOP of 14.57, mean last IOP of 13.79, and a mean IOP of 14.14 during aflibercept treatment. The inference is based on the pooled analysis. The 95% confidence interval for the differences (after minus before) were -0.30 (-1.12 to 0.52), -1.08 (-1.83 to -0.32), and -0.73 (-1.30 to -0.17) for the first, last, and mean IOPs, respectively. The corresponding P values were 0.46 for the first, 0.006 for the last, 0.01 for the mean IOP during the aflibercept treatment period. CONCLUSION: Intraocular pressure was found to be significantly lower in patients switched to aflibercept after previous treatments with ranibizumab and/or bevacizumab. Aflibercept may have a more favorable IOP safety profile in patients previously on other anti-vascular endothelial growth factor treatments.

Retinal vascular abnormalities in neovascular age-related macular degeneration.

PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD). METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts. RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months. CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.

Multifocal choroiditis without panuveitis: clinical characteristics and progression.

PURPOSE: To describe the clinical characteristics and progression of patients with multifocal choroiditis lesions who had minimal or no evidence of anterior uveitis and/or vitritis. METHODS: Retrospective, observational, single-center consecutive case series. Clinical histories, examination, and multimodal imaging findings were analyzed. RESULTS: Sixty-five eyes of 41 patients were identified. The mean age at diagnosis was 38.4 years (median, 35 years; range, 15-81 years), and 70.7% of the patients were women. Involvement was bilateral in 21 patients (51.2%) at presentation. The 60-month bilateral event-free survival was 75.0% (95% confidence interval, 49.8-91.2%). The mean visual acuity was 20/46 (median, 20/25; range, 20/20 to count fingers at 2 feet) at presentation and 20/42 (median, 20/25; range, 20/20-5/400) at the last recorded visit. The 60-month "20/50 or worse" event-free survival was 100%. Between the first presentation and final follow-up (a mean duration of 92.6 months; range, 0-343 months), 46.7% of the eyes developed new or larger chorioretinal spots and 32.6% developed new or recurrent choroidal neovascularization. The 60-month choroidal neovascularization event-free survival was 68.1% (95% confidence interval, 39.2-85.4%). CONCLUSION: Patients with multifocal choroiditis lesions, but with minimal or no anterior uveitis or vitritis, tended to be young women. Approximately half of the patients presented with bilateral involvement, which is less than has been reported in most case series of multifocal choroiditis with panuveitis. One quarter of all unilaterally affected patients will develop bilateral involvement by 60 months.

Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 12 optical coherence tomography and fluorescein angiography.

PURPOSE: To report the optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) results of the Macular Epiretinal Brachytherapy in Treated Age-Related Macular Degeneration study. DESIGN: Prospective, multicenter, interventional, noncontrolled clinical trial. PARTICIPANTS: Fifty-three eyes of 53 participants with chronic, active neovascular age-related macular degeneration (AMD) requiring frequent anti-vascular endothelial growth factor retreatment. METHODS: Participants underwent pars plana vitrectomy with a single 24-gray dose of epimacular brachytherapy (EMB), delivered with an intraocular, handheld, cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were retreated with ranibizumab administered monthly as needed, using predefined retreatment criteria. Patients underwent FFA at baseline, month 1, and month 12. Patients underwent optical coherence tomography (OCT) at baseline and then monthly for 12 months. The FFA and OCT images were evaluated by independent, central reading facilities. MAIN OUTCOME MEASURES: Change in OCT centerpoint thickness and angiographic lesion size 12 months after EMB. RESULTS: Mean centerpoint thickness increased by 50 µm, from 186 to 236 µm (P = 0.292), but 70% of participants had an increase of less than the mean, with a median increase of only 1.8 µm. The FFA total lesion size increased slightly by 0.79 mm(2), from 14.69 to 15.48 mm(2) (P = 0.710). Total choroidal neovascularization (CNV) area increased by 1.17 mm(2), from 12.94 to 14.12 mm(2) (P = 0.556). The classic CNV area decreased substantially by 3.70 mm(2), from 3.90 to 0.20 mm(2) (P<0.01). Predominantly classic lesions showed the greatest response, with mean Early Treatment Diabetic Retinopathy Study visual acuity improving by 1.5 letters (versus -4.0 for all participants combined); mean centerpoint thickness decreased by 43 µm (P = 0.875). The angiographic and OCT response did not correlate with lesion size at baseline. CONCLUSIONS: In chronic, active, neovascular AMD, EMB is associated with nonsignificant changes in centerpoint thickness and FFA total lesion size over 12 months.

Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography.

PURPOSE: To report the fluorescein angiography (FA) and optical coherence tomography (OCT) results of a clinical trial of epimacular brachytherapy (EMBT) used for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Pivotal multicenter, active-controlled, randomized clinical trial. PARTICIPANTS: A total of 494 participants with treatment-naïve, neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized to receive (a) EMBT and 2 mandated monthly ranibizumab injections followed by pro re nata (PRN) ranibizumab or (b) 3 mandated monthly ranibizumab injections followed by mandated quarterly plus PRN ranibizumab. Participants underwent FA at screening and at months 1, 6, 12, 18, and 24. Optical coherence tomography scans were undertaken monthly for 24 months. The FA and OCT images were analyzed at respective independent reading centers. MAIN OUTCOME MEASURES: Change at 24 months in mean FA total lesion size and choroidal neovascularization (CNV) size and change in mean OCT centerpoint thickness. RESULTS: The mean (standard deviation) changes in FA total lesion size in the EMBT and control arms were +1.9 (8.7) and -3.0 (7.2) mm(2), respectively, with a mean change in total CNV size of +0.4 (8.4) and -4.7 (6.5) mm(2), respectively. Mean (standard deviation) changes in OCT centerpoint thickness were -144 (246) and -221 (185) µm, respectively. Retrospective subgroup analyses showed no significant difference between treatment arms in mean centerpoint thickness in some subgroups, including eyes with classic lesions. The control arm showed a significantly larger reduction in mean total lesion size and mean CNV size than the EMBT arm in all subgroups analyzed. Nine eyes in the EMBT arm showed features consistent with mild, nonproliferative radiation retinopathy, but with a mean gain of 5.0 Early Treatment Diabetic Retinopathy Study letters. CONCLUSIONS: Both FA and OCT suggest that EMBT with PRN ranibizumab results in an inferior structural outcome than quarterly plus PRN ranibizumab. Some subgroup analyses suggest that classic lesions may be more responsive than occult lesions, although generally both subgroups are inferior to ranibizumab. A non-vision-threatening radiation retinopathy occurs in 2.9% of eyes over 24 months, but longer follow-up is needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (nvAMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: Two hundred thirty patients with onset of nvAMD within 3 years who received 3 or more injections of ranibizumab or bevacizumab within the preceding year and who needed continuing ranibizumab or bevacizumab treatment. INTERVENTIONS: Participants were randomized 2:1:2:1 to 16 Gy plus pro re nata (PRN) ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, or sham 24 Gy plus PRN ranibizumab, respectively. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean number of ranibizumab injections at 52 weeks. Secondary end points were change in mean best-corrected visual acuity (VA), loss of fewer than 15 Early Treatment Diabetic Retinopathy Study letters, gain of 0 or more and 15 or more letters, and change in angiographic total lesion size and choroidal neovascularization (CNV) lesion size. RESULTS: Both the 16-Gy and 24-Gy SRT arms received significantly fewer ranibizumab treatments compared with the sham arms: mean number of treatments, 2.64 (median, 2), 2.43 (median, 2), and 3.74 (median, 3.5), respectively (P = 0.013 and P = 0.004, respectively, vs. sham). Change in mean VA was -0.28, +0.40, and -1.57 letters for the 16-Gy, 24-Gy, and sham arms, respectively. The 16-Gy, 24-Gy, and sham arms lost fewer than 15 letters in 93%, 89%, and 91% of eyes, respectively, with 53%, 57%, and 56% gaining 0 or more letters, respectively, and 4% gaining 15 letters or more in all arms. Mean total angiographic lesion area changed by -1.15 mm(2), +0.49 mm(2), and +0.75 mm(2), respectively; mean CNV lesion area decreased by 0.16 mm(2), 0.18 mm(2), and 0.10 mm(2), respectively. Optical coherence tomography central subfield thickness decreased by 85.90 µm, 70.39 µm, and 33.51 µm, respectively. The number of adverse events (AEs) and number of serious AEs (SAEs) were similar across arms. No AEs were attributed to radiation. No SAEs occurred in the study eye. CONCLUSIONS: A single dose of SRT significantly reduces ranibizumab retreatment for patients with nvAMD, with a favorable safety profile at 1 year. Whereas chronic nvAMD typically results in loss of VA over time, SRT is associated with relatively well-preserved VA over 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study.

PURPOSE: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial. PARTICIPANTS: Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105). METHODS: Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months. MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment-free interval of 3 months or longer. RESULTS: Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (-7.90 to infinity); P = 0.0666; and 97.5% CI, (-8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 µm and 140.9 µm for the verteporfin SF and RF groups, respectively, and by 172.2 µm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases. CONCLUSIONS: Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated.

Solar retinopathy: a photobiologic and geophysical analysis. 1989.

A series of young adult patients developed solar retinopathy during sun exposure over a two-day period in a particular region of the United States during March of 1986. Evaluation of the photobiological and geophysical parameters involved in solar retinitis are presented. A multifactorial pathogenesis is proposed. Of interest, a possible increase in terrestrial ultra-violet B radiation secondary to a localized relatively low ozone column during the days involved may have contributed to the retinal damage. Recommendations for protection from solar retinitis are noted.

Digital indocyanine green videoangiography and choroidal neovascularization. 1992.

This report describes a new system for digital indocyanine green videoangiography (ICGV) that provides enhanced imaging of the choroidal circulation. This newly assembled system was used to study a consecutive series of 129 patients with exudative age-related macular degeneration (AMD), and ill-defined or occult choroidal neovascularization (CNV). Overall, 39% of the patients in this study with occult CNV could be reclassified as having well-delineated or so-called classic CNV by virtue of the additional findings provided by ICGV. In this series, ICGV was particularly useful in identifying occult CNV in eyes with a large, serous pigment epithelial detachment (PED) and in eyes with recurrent CNV after previous laser photocoagulation treatment. Some of these patients were selected for laser photocoagulation of the abnormal choroidal vessels in order to evaluate the feasibility of this form of treatment on the basis of combined clinical, fluorescein angiographic, and ICGV findings. The results of this study suggest that ICGV is an important adjunct in the evaluation, classification, and laser treatment of patients with occult CNV secondary to AMD.

Indocyanine green angiography-guided photodynamic therapy for treatment of chronic central serous chorioretinopathy: a pilot study. 2003.

BACKGROUND: Most patients with central serous chorioretinopathy (CSC) have spontaneous resolution of exudative macular detachments and a good visual prognosis. Patients with CSC have a primary choroidal hyperpermeability problem evident as multifocal areas of hyperpermeability during indocyanine green (ICG) angiography. A small percentage of patients develop chronic or progressive disease with widespread decompensation of the retinal pigment epithelium and severe vision loss. There is no known treatment for this variant of the disorder. PURPOSE: To study ICG-guided photodynamic therapy (PDT) with verteporfin as a potential treatment for patients with chronic CSC. METHODS: Twenty eyes of 15 patients were studied with fluorescein angiography, optical coherence tomography, and ICG angiography to diagnose the maculopathy, monitor the detachments, and localize the choroidal hyperpermeability of the disorder. PDT with ICG guidance was applied to areas of choroidal hyperpermeability, and the patients were observed to determine the anatomic and functional outcomes. RESULTS: Photodynamic therapy guided by ICG was associated with complete resolution of exudative macular detachments in 12 patients and incomplete resolution in the remaining eight eyes. The vision improved in six eyes and remained unchanged in 14 eyes during a mean follow-up of 6.8 months. Six weeks after treatment, the mean visual acuity improved by 0.55 lines, an amount that was marginally significant. There was a significant inverse correlation between the baseline visual acuity and the amount of improvement in acuity at 6 weeks. No patient had any treatment-related side effects. CONCLUSIONS: Indocyanine green angiography-guided PDT with verteporfin seems to aid in the resolution of exudative detachments in patients with chronic CSC. This treatment was associated with a rapid reduction in subretinal fluid and improvement in visual acuity. Although the follow-up time and number of patients in this pilot study were limited, the encouraging results and lack of complications suggest that further study is indicated.