Volume 15, Number 4April 2019THE LATEST PUBLISHED RESEARCH WELCOME to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease. INSIDE THIS ISSUE:
HAWK and HARRIER: Trials of Brolucizumab for nAMDTwo similarly designed, Phase III trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration, as part of double-masked, multicenter, active-controlled, randomized trials sponsored by brolucizumab’s maker, Novartis. Participants (n=1,817) included individuals with untreated, active choroidal neovascularization due to AMD in the study eye. Individuals were randomized to intravitreal brolucizumab 3 mg (HAWK only), 6 mg or aflibercept 2 mg. After loading with three monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval-adjusted to every eight weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing. The primary hypothesis was noninferiority in the mean best-corrected visual acuity change from baseline to week 48 (margin: four letters). Other key endpoints included the percentage of individuals who maintained q12w dosing through week 48 and anatomical outcomes. Here were some of the findings: Researchers wrote that anti-VEGF rescue therapy has a potential role in select cases of laser treated PDR with persistent new vessels, and no evidence of traction to achieve regression of neovascularization. Port Delivery System with Ranibizumab for nAMD: Ladder Clinical TrialResearchers analyzed the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration, as part of the Genentech-sponsored Ladder trial, a Phase II, multicenter, randomized, active treatment-controlled clinical study. Participants included individuals diagnosed with nAMD within nine months, who had received ≥2 prior anti-vascular endothelial growth factor intravitreal injections and who were responsive to treatment. Subjects were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/mL, 40 mg/mL and 100 mg/mL formulations, or monthly intravitreal ranibizumab 0.5 mg injections. Main outcome measures included time to first implant refill assessed when the last enrolled subject completed the nine-month visit, improvements in best-corrected visual acuity and central foveal thickness, and certain safety benchmarks. The primary analysis population included 220 individuals, in the following breakdown: (using the PDS) 58 subjects in the 10 mg/mL arm; 62 subjects in the 40 mg/mL arm; 59 subjects in the 100 mg/mL arm; and 41 subjects in the monthly intravitreal ranibizumab 0.5 mg arm. Here are some of the findings:
• With the PDS, median time to first implant refill was 8.7 months in the 10 mg/mL arm, 13 months in the 40 mg/mL arm and 15 months in the 100 mg/mL arm.
Researchers determined in the Phase II Ladder trial that the PDS was generally well-tolerated and demonstrated a dose response across multiple endpoints in individuals with nAMD. They found that the PDS 100 mg/mL arm had visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5 mg injections, but with a reduced total number of ranibizumab treatments. Researchers wrote that the PDS had the potential to reduce treatment burden in nAMD while maintaining vision. Reactivation in Type 3 Neovascularization After Initial TreatmentInvestigators evaluated the long-term incidence and timing of reactivation in individuals with type 3 neovascularization who were treated with three monthly anti-vascular endothelial growth factor injections. A total of 179 individuals (179 eyes) diagnosed with type 3 neovascularization with a dry macula after three monthly anti-VEGF loading injections were included in this retrospective study. After the initial treatment, individuals were followed up without further injection until the first reactivation. Investigators recorded the incidence and timing of the first reactivation and assessed factors predictive of early reactivation (≤ six months after the third anti-VEGF injection). Here were some of the findings: • During a mean follow-up of 37.5 ±18.8 months, the first reactivation was noted in 145 subjects (81 percent) at a mean of 6.6 ±4.1 months after the third injection.
Investigators found that, in individuals with type 3 neovascularization, almost all reactivation was detected within 15 months of the third anti-VEGF injection, suggesting the need for close follow-up and detailed examinations during this period. They recommended that females with thick choroids be monitored more frequently during this early period. Association of CD11b+ Monocytes and Anti-VEGF Injections in Treating nAMD & PCVResearchers looked at whether the proportion of CD11b+ circulating monocytes was associated with the number of anti-vascular endothelial growth factor injections in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. The observational cohort study collected data from Jan. 1, 2010, through Dec. 31, 2013, and from Jan. 1, 2015, through Dec. 31, 2018. Fresh venous blood samples were acquired for flow cytometric immune studies in individuals with neovascular AMD or PCV receiving treatment with aflibercept or ranibizumab as needed for 36 months. Individuals (n=81) without immune diseases were consecutively recruited from a single center in Denmark. Main outcomes and measures included estimation of the number of intravitreal anti-VEGF injections given at 12, 24 and 36 months by the proportion of CD11b+ circulating monocytes and the correlation between these values. The angiogenic role of CD11b+ circulating monocytes was further evaluated by investigating the expression of the known proangiogenic receptor CCR2. Eighty-one individuals were included in the analysis (54 percent women; mean age: 76 ±7] years). Here were some of the findings:• The proportion of CD11b+ monocytes at baseline positively estimated the future number of anti-VEGF injections at 12 months (ρ=0.77; CI, 0.35 to 0.93; p=0.004), 24 (ρ=0.82; CI, 0.44 to 0.95; p=0.002) and 36 months (ρ=0.78; CI, 0.34 to 0.94; p=0.005). Researchers wrote that the proportion of circulating CD11b+ monocytes estimated and correlated with the number of anti-VEGF injections in individuals with neovascular AMD and PCV. They added that additional longitudinal studies would be needed to determine whether the findings had clinical relevance to influence treatment algorithms or provide novel targets for medical therapy. Precursors & Development of GA with Autofluorescence ImagingResearchers described the sequence of events leading to development of geographic atrophy in age-related macular degeneration with fundus autofluorescence imaging, as part of a post hoc analysis of FAF images from the Age-Related Eye Disease Study 2. FAF images of 120 eyes (109 individuals) with incident GA and at least two years of preceding FAF images were included. Researchers stacked and aligned images of incident GA over FAF images of preceding annual visits. They assessed regions of retina that developed into incident GA on prior years' FAF images. These regions, defined as precursor lesions, were classified as Minimal ChangeAF, Predominant HypoAF (decreased AF), Predominant HyperAF (increased AF) and MixedAF. Researchers evaluated the natural progression in precursor lesions leading to GA formation, and associations with incident GA size and GA enlargement rate. Here were some of the findings: • Incident GA had a mean area of 1.00 mm2 (range: 0.15 to 8.22 mm2) and an enlargement rate of 0.97 mm2/year (SD 1.66).
Researchers used image registration to identify changes in AF mages prior to onset of GA. They reported that decreased autofluorescence was the most common change, although minimal changes were also seen in a third of the images. In addition, they found that incident GA that arose from predominantly normal AF was associated with faster enlargement rates compared with GA arising from abnormal AF. Finally, researchers noted that faster GA enlargement rates were also associated with incident GA size, area of surrounding abnormal autofluorescence and presence of reticular pseudodrusen. Features of RPE & Chorioretinal Characteristics in Eyes with Early AMD & Subretinal Drusenoid DepositsResearchers assessed the features of the retinal pigment epithelium on optical coherence tomography in eyes with early age-related macular degeneration and subretinal drusenoid deposits. Investigators counted the number of type 3 neovascularization lesions and estimated the incidence of multiple lesions in an eye. In addition, they estimated the distance from the fovea to the lesion, and the geographic location of the lesion. They classified the eyes into three types: nonundulating RPE; undulating RPE; and wedge-shaped RPE. They also compared the retinal vessel densities, retinal thickness and choroidal thickness in a 3-mm-diameter zone. • A total of 33 eyes were classified as nonundulating RPE, 27 eyes were classified as undulating RPE and 20 eyes were identified as wedge-shaped RPE eyes.
Researchers reported that altered features of the RPE on optical coherence tomography might indicate advancement in disease and be part of an overall degeneration process in these eyes. Retinal Nonperfusion Characteristics on Ultra-widefield Angiography in Severe NPDR and PDRInvestigators identified a threshold of retinal nonperfusion for the presence of retinal neovascularization, and the distribution and area of retinal nonperfusion in eyes with severe nonproliferative diabetic retinopathy, PDR, neovascularization of the optic disc (NVD) and retinal neovascularization elsewhere (NVE). This cross-sectional image analysis was performed between Sept. 24, 2018, and Oct. 24, 2018, in a multicenter national study in the United Kingdom. Baseline images were obtained from two completed randomized clinical trials (Ranibizumab for Diabetic Macular Edema Panretinal Photocoagulation [RDP] study and Clinical Efficacy of Intravitreal Aflibercept vs. Panretinal Photocoagulation for Best Corrected Visual Acuity in Patients With Proliferative Diabetic Retinopathy at 52 Weeks [CLARITY] study). The RDP study recruited eyes with severe NPDR between April 1, 2014, and Dec. 31, 2015, and the CLARITY study recruited eyes with PDR between Aug. 22, 2014, and Nov. 20, 2015. The study included ultra-widefield angiography images of eyes with no prior panretinal photocoagulation treatment. Main outcomes and measures included the total area of retinal nonperfusion, the area of posterior pole retinal nonperfusion and the area of peripheral retinal nonperfusion. A total of 92 individuals (92 eyes) were included in the study: 59 in the PDR group (mean age: 42 ±15 years; 20 female [33.9 percent] and 33 in the NPDR group (mean age: 63 ±10 years; 30 female [9.1 percent]). Forty eyes had NVE and 19 had NVD with or without NVE. Here were some of the findings: • Investigators identified a retinal nonperfusion threshold of 118.3 disc areas with a specificity of 84.9 percent (CI, 68.1 to 94.9 percent) for PDR.
SOURCE: Nicholson L, Ramu J, Chan EW, et al. Retinal nonperfusion characteristics on ultra-widefield angiography in eyes with severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. JAMA Ophthalmol 2019; Apr 11. [Epub ahead of print]. ICGA-guided Focal Navigated Laser Photocoagulation for DMEResearchers evaluated the efficacy of indocyanine-green angiography-guided navigated focal laser photocoagulation for diabetic macular edema, as part of a prospective, interventional case series. Six individuals (eight eyes) were enrolled in the study. Researchers performed fluorescein angiography and ICGA using the Heidelberg Retina Angiogram 2. They delivered navigated focal laser photocoagulation to the microaneurysms on ICGA using the Navilas system (OD-OS). Researchers measured central retinal thickness and macular volume by the Cirrus HD-OCT (Carl Zeiss Meditec). At six months, they compared the best-corrected visual acuity, CRT and MV to the values measured prior to procedures. They measured distances from the center of the fovea to the closest microaneurysms on pre-planned Navilas images. All eyes had a previous treatment history. Here were some of the findings: • At six months, ICGA-guided navigated focal laser photocoagulation significantly reduced the CRT and MV (p<0.05), and improvement was found in the BCVA (p<0.05).
Researchers determined that their data suggests that ICGA-guided navigated focal laser photocoagulation might be effective for the treatment of DME. Posteriorly Inserted Vitreous Base After VitrectomyInvestigators determined the preoperative characteristics, intraoperative and postoperative complications, and outcomes of eyes with a posteriorly inserted vitreous base. In the retrospective, observational, consecutive case series at two academic centers, 37 individuals were studied who had a posteriorly inserted vitreous base noted during vitrectomy. A posteriorly inserted vitreous base was defined as posterior hyaloid membrane insertion located posterior to the vortex veins. Fifteen eyes were analyzed in a histopathologic study of donor eyes to determine the average distance of the ora serrata from the vortex veins, as investigators noted that this distance was uncertain. Here were some of the findings: • A posteriorly inserted vitreous base was identified during vitrectomy in the following eyes: 31 with rhegmatogenous retinal detachment (84 percent); four with macular holes (11 percent); one with vitreous hemorrhage; and one with epiretinal membrane.
Investigators determined that any eye undergoing vitrectomy might have a posteriorly inserted vitreous base, but those with a high number of retinal breaks and lattice near the equator might be at highest risk. They added that redetachment and proliferative vitreoretinopathy still occurred in the study, despite knowledge of the disorder and adjuvant treatments. NOTEWORTHY NOVARTIS ANNOUNCES FDA FILING OF BROLUCIZUMAB
Novartis announced that the FDA accepted the company's Biologics License Application for brolucizumab (RTH258) for the treatment of wet age-related macular degeneration. Seeking to make brolucizumab available as quickly as possible, Novartis used a priority review voucher to expedite FDA review. If approved by the FDA, Novartis anticipates launching brolucizumab by the end of 2019. The regulatory application is primarily based on Phase III data from the HAWK and HARRIER trials (described above). The primary endpoint of these studies was non-inferiority to aflibercept in mean change in best-corrected visual acuity from baseline to week 48. HAWK and HARRIER are the first and only global head-to-head trials in patients with wet AMD that prospectively demonstrated efficacy at week 48 starting with a 12-week dosing regimen, Novartis says. Read more. SOURCE: Novartis, April 2019
B+L LAUNCHES LOTEMAX SM 0.38%
Alcon Debuts as Independent Company OPHTHOTECH OBTAINS EXCLUSIVE GLOBAL LICENSE TO AAV GENE THERAPY PROGRAM FOR BEST1-RELATED RETINAL DISEASES Ophthotech announced that the company entered into an exclusive global license agreement with the University of Pennsylvania, including the Perelman School of Medicine at the University of Pennsylvania, the University of Pennsylvania School of Veterinary Medicine and the University of Florida Research Foundation, for rights to develop and commercialize novel adeno-associated virus gene therapy product candidates for the treatment of Best vitelliform macular dystrophy and other diseases related to mutations to the BEST1 gene. Read more. Source: Ophthotech, April 2019 AERIE INITIATES PHASE II CLINICAL TRIAL OF AR-1105 Aerie Pharmaceuticals commenced patient dosing in a Phase II clinical trial of AR-1105, its investigational dexamethasone intravitreal implant, in individuals with macular edema due to retinal vein occlusion. The study will be conducted at approximately 20 centers in the United States and enroll up to 45 patients. The primary objectives of the trial are to evaluate the safety, tolerability and efficacy of the AR-1105 dexamethasone intravitreal implant. The study will be conducted in two stages. Read more. SOURCE: Aerie Pharmaceuticals, March 2019 AERPIO DRUG DOESN’T MEET PRIMARY ENDPOINT IN DIABETIC RETINOPATHY Aerpio Pharmaceuticals announced that the company’s TIME-2b study, a Phase IIb clinical trial designed to assess the efficacy and safety of its lead candidate, AKB-9778, for moderate to severe non-proliferative diabetic retinopathy didn’t meet the primary endpoint. Administration of AKB-9778 twice daily didn’t increase the percentage of patients with an improvement of two or more steps in the study eye’s diabetic retinopathy severity score compared with placebo. Read more. Source: Aerpio Pharmaceuticals, March 2019 OXURION ENROLLS PATIENTS FOR PHASE II TRIAL EVALUATING COMBINATION OF ANTI-PLGF (THR-317) AND ANTI-VEGF (RANIBIZUMAB) FOR DME TREATMENT Oxurion announced that all patients were enrolled in its Phase II trial evaluating its THR-317, a humanized antibody against placental growth factor, in combination with anti-VEGF (ranibizumab) for the treatment of diabetic macular edema. A total of 70 individuals were enrolled in the study. Topline data from the study are expected by the third quarter of 2019. Read more. STUDY: LIGHT THERAPY MIGHT HELP PREMATURE BABIES AVOID VISION PROBLEMS Researchers at Cincinnati Children's Hospital Medical Center discovered a light-dependent molecular pathway that regulates how blood vessels develop in the eye. The findings in the April 1 online edition of Nature Cell Biology suggested that light therapy might help premature infants avoid vision problems. The novel molecular process called the opsin 5-dopamine pathway helps ensure blood-vessel development in the eye is appropriately balanced to prepare it for visual function. Researchers are looking for ways to prevent or treat retinopathy of prematurity and myopia in premature infants. Read more. Review of Ophthalmology's® Retina Online is published by the Review Group, a Division of Jobson Medical Information LLC (JMI), 11 Campus Boulevard, Newtown Square, PA 19073. |