Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy
OBJECTIVE:Evaluate clinical characteristics of eyes that developed investigator-determined new-onset exudative age-related macular degeneration (eAMD) during the FILLY trial. DESIGN/METHODS:Post-hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS/METHODS:246 subjects with GA secondary to AMD. INTERVENTION/METHODS:Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month (EOM) for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES/METHODS:Time of onset of new eAMD in the study eye; history of eAMD in the fellow eye; presence of double layer sign (DLS) on structural optical coherence tomography (OCT) in the study eye; changes in retinal anatomy by structural OCT and fluorescein angiography (FA); and changes in visual acuity. RESULTS:Exudation was reported in 26 study eyes across all treatment groups over 18 months. Mean time to diagnosis of eAMD was 256 days (range: 31 to 555). Overall, a higher proportion of subjects with a history of eAMD in the fellow eye (P=0.016) and a DLS in the study eye at baseline (P=0.0001) developed eAMD. Among study eyes that developed eAMD, 18/26 (69%) had a history of fellow eye eAMD and 19/26 (73.1%) had a DLS at baseline, compared to 72/217 (33%) (P=0.0003) and 70/215 (32.5%) (P<0.0001)respectively, of study eyes that did not develop eAMD. All 21 subjects with structural OCT imaging at the time of eAMD diagnosis had subretinal fluid and/or intraretinal cysts, consistent with exudation. Among 17 subjects who received FA at the time of eAMD diagnosis, 10 had detectable MNV, all occult lesions. Development of eAMD did not appear to have an appreciable impact on visual acuity, and all subjects responded to anti-VEGF therapy. CONCLUSIONS:Intravitreal injections of pegcetacoplan slowed the rate of GA growth and were associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. eAMD appeared to be associated with the presence of 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.
Safety and Efficacy of Subretinally Administered Palucorcel for Geographic Atrophy of Age-Related Macular Degeneration: Phase 2b Study
PURPOSE/OBJECTIVE:To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue-derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). DESIGN/METHODS:Multicenter, open-label phase 2b study. PARTICIPANTS/METHODS:Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. METHODS:cells in 50 Î¼l, using the custom-designed delivery system and surgical procedure. MAIN OUTCOME MEASURES/METHODS:Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. RESULTS:and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (nÂ = 5), retinal hemorrhage (nÂ = 4), and vitreous floaters (nÂ = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was -5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and -3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. CONCLUSIONS:Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.
Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial
PURPOSE/OBJECTIVE: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/METHODS:Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS/METHODS: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/METHODS: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; PÂ = 0.008) and 20% (95% CI, 0-40; PÂ = 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% (PÂ = 0.0004) and 33% (PÂ = 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.
Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers
INTRODUCTION/BACKGROUND:Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. OBJECTIVE:This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. METHODS:This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. RESULTS:One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. CONCLUSION/CONCLUSIONS:There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).
Predictors of visual outcomes in patients with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapy: post hoc analysis of the VIEW studies
PURPOSE/OBJECTIVE:Identify predictors for response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular (wet) age-related macular degeneration (nAMD). METHODS:Retrospective, post hoc analysis of VIEW 1/2. Patients were randomized 1:1:1:1 to 0.5Â mg intravitreal aflibercept (IVT-AFL) injection every 4Â weeks (0.5q4); 2Â mg IVT-AFL every 4Â weeks (2q4); 2Â mg IVT-AFL every 8Â weeks (2q8) after an initial three injections at weeks 0, 4 and 8 or 0.5Â mg intravitreal ranibizumab every 4Â weeks (0.5q4). RESULTS:1815 patients [IVT-AFL 2q4 (nÂ =Â 613); IVT-AFL 2q8 (nÂ =Â 607); ranibizumab 0.5q4 (nÂ =Â 595)] were included. Baseline demographics/characteristics were evenly balanced. Younger age (49-69Â years), lower visual acuity (VA) [10.0-â‰¤45.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and smaller choroidal neovascularization (CNV) size [0.0-â‰¤3.1 disc areas (DA)] at baseline were associated with the most vision gain (â‰¥15 letters) over 52Â weeks (all nominal pÂ <Â 0.0001).Younger age, higher baseline VA (>64.0-â‰¤83.0 letters) and smaller CNV size were associated with a VA â‰¥20/40 at week 52. Predominantly classic CNV at baseline (nominal pÂ =Â 0.0007), older age (â‰¥90Â years), lower baseline VA (10.0-â‰¤ 45.0 ETDRS letters) and larger CNV size (>10.1-â‰¤32.6 DA) were all associated with a VA â‰¤20/200 at week 52 (all nominal pÂ <Â 0.0001). Along with treatment (nominal pÂ <Â 0.0001), lower VA (pÂ =Â 0.0166) and smaller central retinal thickness (both nominal pÂ =Â 0.0190) were predictors for dry retina development. CONCLUSION/CONCLUSIONS:Younger age, lower VA and smaller CNV size at baseline were all associated with greater vision gains over 52Â weeks while younger age, higher VA and smaller CNV size at treatment start were more likely to achieve best-corrected VA 20/40 or better after a year's treatment, suggesting the benefit of early anti-VEGF treatment.
Treatment of juxtapapillary hemangioblastoma by intra-arterial (ophthalmic artery) chemotherapy with bevacizumab
Purpose/UNASSIGNED:To report on two cases of treatment-refractory juxtapapillary hemagioblastomas that were managed with intra-arterial bevacizumab delivered via the ophthalmic artery. Observations/UNASSIGNED:Case 1 is a 35 year-old man with juxtapapillary hemangioblastoma who continued to have progressive tractional retinal detachment, optic nerve neovascaularization and cystoid macula edema (CME) despite heavy prior treatment with intravitreal anti-vascular endothelial growth factor (VEGF) and steroid intravitreal injections and laser. Case 2 is a 41 year-old woman with juxtapapillary hemangioblastoma who had progressive tractional retinal detachment, CME and visually-threatening intraocular pressure elevation despite treatment with anti-VEGF injection and laser. Both cases were treated with three infusions of intra-arterial bevacizumab delivered via the ophthalmic artery. Both tumors demonstrated measurable decrease in height, stability of their secondary retinal changes and minimal requirement for additional treatment at 30 mos and 26 mos follow-up, respectively for cases 1 and 2. Conclusions and importance/UNASSIGNED:These cases suggest that higher-dose, targeted delivery of anti-VEGF to hemangioblastomas via ophthalmic artery injection may be useful in stabilizing the disease and abating the typical progression of secondary retinal pathology, at least in the first two years after treatment.
FULL-THICKNESS MACULAR HOLE COMBINED WITH PIGMENT EPITHELIAL DETACHMENT USING MULTIMODAL IMAGING
PURPOSE: To describe two patients who showed full-thickness macular holes (FTMH) combined with pigment epithelial detachments (PED) and had contrasting outcomes to treatment. METHODS: A retrospective report of two cases. RESULTS: Case 1 was treated with intravitreal antivascular endothelial growth factor and photodynamic therapy, and the PED flattened. Subsequently, a vitrectomy was performed and the FTMH closed. Her visual acuity improved from 20/200 to 20/25. In Case 2, the same medical therapy, with less frequency compared with Case 1, did not affect the PED, and the FTMH failed to close with surgery. Later, a spontaneous collapse of the PED occurred but the FTMH was persistent with an associated poor visual acuity of 20/200. CONCLUSION: Full-thickness macular hole is rare, but can occur in association with large PEDs. Although the pathologic mechanism was uncertain, visual outcomes were dependent on response to treatments of the PED, as well as anatomical closure of the FTMH.
Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study
Importance/UNASSIGNED: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/UNASSIGNED:To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD. Design, Setting, and Participants/UNASSIGNED: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/UNASSIGNED:Participants received oral X-82 for 24 weeks at 50 mg alternate days (nâ€‰=â€‰3), 50 mg daily (nâ€‰=â€‰8), 100 mg alternate days (nâ€‰=â€‰4), 100 mg daily (nâ€‰=â€‰10), 200 mg daily (nâ€‰=â€‰7), and 300 mg daily (nâ€‰=â€‰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/UNASSIGNED:The main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections. Results/UNASSIGNED: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  Î¼m, 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 (nâ€‰=â€‰6), nausea (nâ€‰=â€‰5), fatigue (nâ€‰=â€‰5), and transaminase elevation (nâ€‰=â€‰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 (nâ€‰=â€‰2), elevated alanine aminotransferase (nâ€‰=â€‰2), diarrhea (nâ€‰=â€‰1), and nausea/anorexia (nâ€‰=â€‰1). Conclusions and Relevance/UNASSIGNED: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.
The Evolution of the Plateau, an Optical Coherence Tomography Signature Seen in Geographic Atrophy
Purpose: Histologic details of progression routes to geographic atrophy (GA) in AMD are becoming available through optical coherence tomography (OCT). We studied the origins and evolution of an OCT signature called plateau in eyes with GA and suggested a histologic correlate. Methods: Serial eye-tracked OCT scans and multimodal imaging were acquired from eight eyes of seven patients with GA and plateau signatures over a mean follow-up of 7.7 years (range, 3.7-11.6). The histology of unrelated donor eyes with AMD was reviewed. Results: Drusenoid pigment epithelial detachment (PED) on OCT imaging progressed into wide-based mound-like signatures with flattened apices characterized by a hyporeflective yet heterogeneous interior and an overlying hyperreflective exterior, similar to outer retinal corrugations previously ascribed to persistent basal laminar deposit (BLamD) but larger. These new signatures are described as "plateaus." An initial increase of the PED volume and hyporeflectivity of its contents was followed by a decrease in PED volume and thinning of an overlying hyperreflective band attributable to the loss of the overlying RPE leaving persistent BLamD. Both imaging and histology revealed persistent BLamD with defects through which gliotic Muller cell processes pass. Conclusions: Plateaus can be traced back to drusenoid PEDs on OCT imaging. We hypothesize that during progressive RPE atrophy, Muller cell extension through focal defects in the residual persistent BLamD may contribute to the heterogeneous internal reflectivity of these entities. The role of Muller cell activation and extension in the pathogenesis of AMD should be explored in future studies.
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.