Volume 17, Number 5May 2021THE 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:
Efficacy and Safety of Intravitreal Aflibercept Using a T&E Regimen for nAMD: The Aries StudyTreating neovascular age-related macular degeneration with intravitreal aflibercept using a treat-and-extend regimen can reduce treatment burden. ARIES investigators assessed whether AFL early-start T&E was noninferior to late-start T&E. The randomized, open-label, Phase IIIb/IV study included treatment-naïve patients ages ≥50 years with best-corrected visual acuity of 73 to 25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg IVT-AFL at week 0, W4, W8 and W16. At W16, patients were randomized 1:1 to early-start (two-week interval adjustments) or late-start T&E (eight-week intervals until W48, then two-week interval adjustments). The primary endpoint was BCVA change from randomization to W104. A total of 271 patients were randomized. Mean BCVA at baseline was 60.2 ±12.1 letters (early-start T&E) and 61.3 ±10.8 letters (late-start T&E). Here were some of the findings: Investigators determined that outcomes were similar between nAMD patients treated with an IVT-AFL early- or late-start T&E regimen following initial dosing, with one injection difference over two years. SOURCE: Mitchell P, Holz FG, Hykin P, et al. Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: The Aries study. Retina 2021; Mar 22. [Epub ahead of print].Impact of Residual Subretinal Fluid Volumes on Outcomes in a SRF-tolerant T&E RegimenResearchers looked at associations between residual subretinal fluid (rSRF) volumes and treatment outcomes in an SRF-tolerant treat-and-extend regimen in neovascular age-related macular degeneration. Patients enrolled in the prospective, multicenter FLUID study randomized in an SRF-tolerant T&E regimen were examined by SD-OCT and tested for best-corrected visual acuity. SRF and intraretinal fluid volumes were quantified using artificial intelligence tools. A total of 375 visits of 98 patients were divided into subgroups: extended intervals despite rSRF and extended intervals without fluid. Associations between BCVA change, SRF volume, subgroups and treatment intervals were estimated using linear mixed models. Here were some of the findings: Researchers reported that AI-based analysis of extended visits despite rSRF demonstrated increasing SRF-volumes associated with BCVA loss at the consecutive visit. They wrote that this negative association increases understanding about the role of rSRF volumes on treatment outcomes in nAMD. SOURCE: Grechenig C, Reiter GS, Riedl S, et al. Impact of residual subretinal fluid volumes on treatment outcomes in a SRF-tolerant treat & extend regimen. Retina 2021; Apr 1. [Epub ahead of print.]
Recurrent nAMD After Discontinuation of VEGF Inhibitors Managed in a T&E RegimenInvestigators assessed the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration previously followed in a treat-and-extend regimen in which treatment had been stopped due to disease stability, as part of a prospective cohort study. A total of 105 nAMD patients previously followed in a treat-and-extend regimen with aflibercept injections were included. All patients with a dry macula on three consecutive visits 12 weeks apart were eligible to participate. Patients were examined at baseline, and then monitored for disease recurrence four, six, eight, 10 and 12 months after the last injection. Main outcome measures included the proportion of patients with recurrent disease within 12 months after the last injection, and BCVA change at the time of recurrence and after resumed therapy. Here were some of the findings: Investigators reported that recurrent nAMD was common in previously stable patients when anti-VEGF injections were suspended. They wrote that it was difficult to predict which patients would have a recurrence, as most didn’t have symptoms in the early stages of reactivation. Investigators stressed the importance of long-term follow-up and noted that early detection of recurrent disease can improve the chances of maintained visual function. SOURCE: Aslanis S, Amrén U, Lindberg C, et al. Recurrent neovascular age-related macular degeneration after discontinuation of VEGF inhibitors managed in a treat and extend regimen. Ophthalmol Retina 2021; Mar 25. [Epub ahead of print].
nAMD Treatment Patterns and Outcomes Over a DecadeManagement of neovascular age-related macular degeneration has evolved over the last decade with several treatment regimens and different medications. This study described the treatment patterns and visual outcomes over 10 years in a large cohort of patients. A retrospective analysis of electronic health records from 27 National Health Service secondary care health-care providers in the UK was undertaken. Participants included treatment-naïve patients receiving at least three intravitreal anti-vascular endothelial growth factor injections for nAMD in their first six months of follow-up. Patients with missing data for age or gender, and those under the age of 55 were excluded. Eyes with at least three years of follow-up were grouped by years of treatment initiation, and three-year outcomes were compared between the groups. Data were generated during routine clinical care between September 2008 and December 2018. Main outcome measures included visual acuity, number of injections and number of visits. A total of 15,810 eyes of 13,705 patients receiving 194,904 injections were included. Here were some of the findings: Investigators wrote that the findings showed that, despite improvement in functional VA over the years, primarily driven by improving baseline VA, patients continued to lose vision after the first year of treatment, with only marginal change over the next decade. They added that the data suggest the results may be related to suboptimal treatment patterns that haven’t improved over the years. They noted that new treatment approaches such as longer-acting therapies may be warranted. SOURCE: Schwartz R, Warwick A, Olvera-Barrios A, et al. Evolving treatment patterns and outcomes of neovascular age-related macular degeneration over a decade. Ophthalmol Retina 2021; Apr 15. [Epub ahead of print].Real-world Outcomes Following Intravitreal Brolucizumab for nAMD: SHIFT StudyBrolucizumab was recently approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration. Investigators reported on early experiences with real-world outcomes of switching to brolucizumab therapy in previously anti-vascular endothelial growth factor-treated patients. Two of the authors received grants from Novartis. Patients with recalcitrant nAMD were switched to brolucizumab. Functional and structural parameters four weeks after the first brolucizumab injection were evaluated, including best-corrected visual acuity (logMAR), foveal center point (FCP [µm]), central subfield retinal thickness (CSRT [µm]) and macular volume (mm³). Sixty-three eyes of 57 patients with nAMD (52.6 percent females) with a mean age of 79.5 ±6.7 years were included. Here were some of the findings: Investigators wrote that the SHIFT study findings indicated that the switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. They suggested that further long-term analyses would be helpful to assess the efficacy and safety of brolucizumab in a routine clinical setting. SOURCE: Bulirsch LM, Saßmannshausen M, Nadal J, et al. Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study. Br J Ophthalmol 2021; Apr 12. [Epub ahead of print]. Hypertension and Wet AMDResearchers aimed to investigate the association between hypertension, wet age-related macular degeneration and the treatment strategy of wet AMD patients affected by hypertension. Data of wet AMD patients at Zhongshan Ophthalmic Center, Sun Yat-sen University, between January 2002 and June 2019, were extracted from the electronic health-care information system. Wet AMD patients were divided into subgroups by hypertension status, age, sex, the need for vitrectomy surgery and the number of anti-VEGF drug intravitreal injections (1 to 3 vs. >3). A total of 3,096 wet AMD patients (41.7 percent female, 58.3 percent male) with an age range of 50 to 96 years (68.7 ±9.42 years) were included. Here were some of the findings: Researchers wrote that wet AMD was associated with hypertension, and wet AMD patients with hypertension were more likely to receive intravitreal anti-VEGF injections than those without hypertension. They suggested that these results may prompt prospective research on the prevention of wet AMD and may aid in the management of wet AMD patients. SOURCE: Wang T, Xia J, Yuan M, et al. Hypertension affects the treatment of wet age-related macular degeneration. Acta Ophthalmol 2021; Mar 31. [Epub ahead of print.]
Choriocapillaris Flow Deficit & Development of Neovascularization or Atrophy in AMDInvestigators evaluated the relationship between choriocapillaris flow deficits and structural optical coherence tomography biomarkers, and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) or macular neovascularization (MNV). Consecutive patients with iAMD were sequentially reviewed to define three equal-sized groups: progressed to MNV; progressed to cRORA; or remained stable over 12 months of follow-up. Odds ratios for progression to cRORA and MNV were estimated by logistic regression for intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDDs), high central drusen volume, fellow eye with late AMD, and peripheral and central choriocapillaris flow deficit. Thirty iAMD eyes from 30 patients were enrolled into each group. Here are some of the findings: Investigators wrote that while the choriocapillaris was diffusely impaired throughout the macula in intermediate AMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy, it was relatively spared in the more peripheral macula among eyes that progressed to MNV. They suggested that these differential findings may have implications for the pathophysiology of the different late-stage manifestations of AMD. SOURCE: Corvi F, Corradetti G, Tiosano L, et al. Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021; Apr 26. [Epub ahead of print]. Topical Ketorolac as an Adjunctive Treatment with Intravitreal Bevacizumab in DME ManagementResearchers evaluated the additional effect of ketorolac eye drops on therapeutic effects of intravitreal bevacizumab in patients with diabetic macular edema. In a randomized clinical trial, 50 patients with center-involved DME (macular thickness ≥300 µm accompanied by decreased VA (24 <BCVA ≤70 ETDRS letters) were enrolled consecutively and randomized 1:1 to receive either bevacizumab plus topical ketorolac (25 patients) or bevacizumab plus artificial tears (25 patients). Patients with proliferative diabetic retinopathy, history of intraocular surgery, intravitreal injection less than three months prior, macular photocoagulation less than six months prior and any other concomitant ocular pathologies were excluded from the study. All patients received three consecutive monthly injections of intravitreal bevacizumab (IVB). After that, patients were examined every six weeks, and reinjection was administered based on the “as needed” protocol if macular thickness was 300 µm or more, and VA was 70 ETDRS letters or less. Patients also received either topical ketorolac or artificial tears three times a day over the study period (six months). Changes in central subfield thickness (CST), best-corrected visual acuity (BCVA, ETDRS letters) and number of IVB injections were compared between the study groups. Fifty eyes of 50 patients were included (25 eyes in each group). Here were some of the findings:
Researchers wrote that topical ketorolac 0.5% three times a day could enhance and sustain the efficacy of intravitreal bevacizumab in the treatment of DME. SOURCE: Nikkhah H, Niazpour Moez R, Entezari M, et al. Topical ketorolac as an adjunctive treatment with intravitreal bevacizumab in the management of diabetic macular edema: A double-masked placebo-controlled randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2021; Apr 15. [Epub ahead of print].
Relationship Between Retinal Vascular Bed Area on WVF FA and DR SeverityResearchers aimed to quantify retinal vascular bed area (RVBA) in square millimeters on stereographically projected ultra-widefield (UWF) fluorescein angiography in eyes with diabetic retinopathy. The prospective, observational study using baseline Optos 200Tx UWF FA images of 80 eyes with DR from the DAVE and RECOVERY studies were stereographically projected at the Doheny Image Reading Center in Los Angeles, to adjust for peripheral distortion. The early-phase FA frame was used to extract the retinal vasculature as a mask for calculating RVBA. The pixels of the retinal vasculature were automatically computed in square millimeters using manufacturer-provided software. Eighteen of 80 diabetic eyes were excluded because image quality and contrast were insufficient for automatic extraction of the retinal vasculature from the background fluorescence. The remaining 62 eyes were included in the final analysis. Here are some of the findings: Researchers found that DR eyes had a larger global retinal vascular bed area for the entire retina than normal controls, and that RVBA appeared to indicate DR severity. However, they noted, the biomarker wasn’t observed to be a good indicator of retinal ischemia. SOURCE: Fan W, Uji A, Nittala M, et al. Retinal vascular bed area on ultra-wide field fluorescein angiography indicates the severity of diabetic retinopathy. Br J Ophthalmol 2021; Apr 7. [Epub ahead of print].Higher Serum Uric Acid Levels and Risk of Vision-threatening DRResearchers looked at the association between serum uric acid levels and vision-threatening diabetic retinopathy in patients with type 2 diabetes. This cross-sectional study evaluated 3,481 patients with type 2 diabetes from four communities in China between 2016 and 2019. Vision-threatening DR was defined as severe nonproliferative or proliferative diabetic retinopathy, or clinically significant macular edema, evaluated by fundus photography and optical coherence tomography. Any potential association between serum uric acid level and vision-threatening DR was examined using multivariable logistic regression. Subgroup analyses based on sex were constructed. Here are some of the findings: Researchers found that higher serum uric acid levels were associated with an increased risk of vision-threatening DR in patients with type 2 diabetes in both sexes, although females seemed to be more sensitive to high serum uric acid levels than males. They suggest that prospective cohort studies will be needed to verify serum uric acid level as a biomarker for predicting the risk of vision-threatening DR, and that further research is needed to determine whether decreasing serum uric acid levels could decrease the risk of vision-threatening DR. SOURCE: Hu Y, Chan Z, Li C, et al. Higher serum uric acid levels are associated with an increased risk of vision-threatening diabetic retinopathy in type 2 diabetes patients. Invest Ophthalmol Vis Sci 2021;62:4:23. [Epub ahead of print.]Computer-aided Detection & Abnormality Score for Outer Retinal Layer on OCTResearchers developed a computer-aided detection (CAD) program of outer retinal layer (ORL) abnormalities in the retinal pigment epithelium, interdigitation zone and ellipsoid zone via optical coherence tomography. In this retrospective study, healthy participants with normal ORL, and patients with ORL abnormality, including choroidal neovascularization or retinitis pigmentosa, were included. First, an automatic segmentation deep learning algorithm, the CAD, was developed for the three outer retinal layers using 120 handcraft masks of ORL. This automatic segmentation algorithm generated 4,000 segmentations, which included 2,000 images with normal ORL and 2,000 (1,000 CNV and 1,000 RP) images with focal or wide defects in ORL. Second, based on the automatically generated segmentation images, a binary classifier (normal vs. abnormal) was developed. Results were evaluated by area under the receiver operating characteristic curve. Here are some of the findings: Researchers wrote that the CAD successfully used OCT images to segment the ORL and differentiate between normal and abnormal ORL areas. They added that the CAD classifier also performed visualization and may aid future physician diagnosis and clinical applications. SOURCE: Rim TH, Lee AY, Ting DS, et al. Computer-aided detection and abnormality score for the outer retinal layer in optical coherence tomography. Br J Ophthalmol 2021 Apr 19. [Epub ahead of print.] Apellis Reports Data from Phase Ib Study of Pegcetacoplan Apellis Pharmaceuticals announced 24-month data from the Phase Ib APL2-103 study of pegcetacoplan (15 mg/0.1 mL), an investigational targeted C3 therapy, in patients with advanced geographic atrophy secondary to age-related macular degeneration and low vision. The main study assessed the safety of the Phase III formulation of the drug. The current post hoc analysis, including eight patients with at least 24 months of data, revealed the growth rate of GA lesions in the treated eye was 46 percent (mean square root) slower than the untreated fellow eye (p=0.007). Read more.
Novartis Phase III Beovu Data Show Potential for Fluid Resolution Novartis announced positive one-year results of the Phase III KESTREL and KITE studies, evaluating the efficacy and safety of Beovu (brolucizumab) 6 mg in diabetic macular edema. Both studies met their primary endpoints of non-inferiority in change in best-corrected visual acuity from baseline for Beovu 6 mg vs. aflibercept 2 mg at year one. Read more.
Lineage Cell Therapeutics Presents Interim Dry AMD Data
SOURCE: Lineage Cell Therapeutics, May 2021
AGTC Reports Data from Ongoing XLRP Trial
TeamedOn and AGTC Advance X-Linked Retinoschisis Gene Therapy TeamedOn International and Applied Genetic Technologies announced a licensing agreement to advance a gene therapy to treat X-linked retinoschisis. Under the terms of the agreement, AGTC will provide TeamedOn with the clinical trial material, and pre-clinical and clinical data generated to develop AGTC’s investigational intravitreal gene therapy candidate, rAAV2tYF-CB-hRS1. Read more. Ocuphire Initiates ZETA-1 Phase II Trial Investigating APX3330 in DR Ocuphire Pharma screened the first patient in ZETA-1, a Phase II trial to evaluate APX3330 in non-proliferative diabetic retinopathy and mild proliferative diabetic retinopathy. Effects on diabetic macular edema will be explored as a secondary outcome. APX3330 is a small molecule oral drug that inhibits the transcription factor regulator Ref-1 (reduction-oxidation effector factor-1). Read more.
Source: Ocuphire, April 2021 ProQR Treatment Shows Benefits in Leber’s Congenital Amaurosis ProQR Therapeutics announced new findings in one patient that indicate vision improvement after treatment with sepofarsen in a clinical trial for CEP290-mediated Leber’s congenital amaurosis 10 (LCA10). The patient, homozygous for the c.2991+1655A>G mutation in CEP290, was part of a larger cohort in the Phase I/II clinical trial, and was studied for 15 months after intravitreal treatment with sepofarsen. The company says that measures of visual function and retinal structure—including visual acuity, light sensitivity and visual fields—reached a substantial efficacy peak near three months after injection and remained better than baseline at 15 months. View the study. Spark Collaborates with Senti Bio to Bolster Gene Therapy Research Spark Therapeutics announced a collaboration and option agreement with Senti Biosciences to apply Senti Bio’s gene circuit technology to the development of gene therapies directed toward specific cell types in the eye and other areas of the body. Read more.SOURCE: Spark Therapeutics, April 2021 Verana Leads Study Showing Promise of Real-world Data in Ophthalmic Clinical Development Verana Health unveiled research during the virtual ARVO meeting demonstrating it was able to successfully use real-world data to replicate primary outcome measures of two large-scale randomized controlled trials in ophthalmology—the VIEW 1 and VIEW 2 pivotal trials. Read more. ForeseeHome AMD Home Monitoring Study Confirms Earlier Results A retrospective study funded by Notal Vision on the use of its ForeseeHome AMD monitoring program found results that were similar to those from the 2014 randomized, controlled AREDS2-HOME study, the company says. Notal says the use of ForeseeHome helped detect wet AMD earlier and with better visual acuity, “a factor previously shown to improve long-term visual outcomes of anti-VEGF treatment.” Read more.SOURCE: Notal Vision, April 2021 Heidelberg and RetInSight to Offer AI-based OCT Fluid Quantification Heidelberg Engineering GmbH and RetInSight GmbH plan to interface RetInSight’s AI-based fluid monitor application with the Heidelberg Engineering product portfolio, using “cloud exchange and application marketplace technologies.” They hope the fluid monitor application will facilitate early diagnosis and therapeutic guidance in common retinal diseases. Read more.SOURCE: Heidelberg Engineering, and RetInSight, April 2021
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