From the editors of Review of Ophthalmology and Retina Specialist
THE 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.
Long-term Retinal Layer Changes in Patients Undergoing Intravitreal Ranibizumab for nAMD
Researchers analyzed long-term changes in retinal layers after intravitreal injections of ranibizumab in individuals with neovascular age-related macular degeneration.
The subjects were treated with 0.5-mg IVRs based on an as-needed protocol after the first three monthly doses over a 12-month follow-up period. Individuals underwent optical coherence tomography and best-corrected visual acuity evaluation at each visit. The ETDRS grid with central subfield (R1) (r 0.5 mm) and the inner ring (R2) (r 0.5 mm to 1.5 mm) was used for calculation of the mean thickness of each RL. Changes in the thickness of segmented RLs within the R1 and R2 of ETDRS circles at months three, six and 12 were compared to baseline.
The mean age was 72 ±7.4 years. The mean number of injections was 9.08 (range: 6 to 11). Here were some of the findings:
• Mean BCVA improved from 49.7 ±22.1 to 60.1 ±19.8 letters.
• Central macular thickness decreased from 390.25 ±149.6 to 312.74 ±118.4 μm.
• Thicknesses of the ganglion cell layer (from 23.93 ±13.73 to 19.50 ±9.50 μm in R1; p=0.001, and from 44.5 ±12.6 to 39.6 ±10.6 μm in R2; p=0.005); inner plexiform layer (from 28.90 ±14.36 to 22.35 ±6.23 μm in R1; p=0.001, and from 39.34 ±8.53 to 35.58 ±7.93 μm in R2; p=0.004); and total inner RL (internal limiting membrane to external limiting membrane) (from 222.93 ±93.09 to 180 ±53 μm in R1; p=0.001, and from 255.06 ±42.74 to 240.25 ±40.37 μm in R2; p=0.003) in the central and parafoveal rings decreased by a statistically significant amount at month-12.
• Decrease in the inner nuclear layer was limited to month six (from 34.80 ±15.33 to 27.60 ±12.59 μm in R1; p=0.001), while decreases in total outer RLs (external limiting membrane to the retinal pigment epithelium) (from 128.32 ±26.92 to 115.54 ±43.98 μm in R1; p=0.001, and 103.81 ±16.73 to 96.38 ±16.22 μm in R2; p=0.014) and RPE (from 39.12 ±22.33 to 29.70 ±22.05 μm in R1; p=0.001, and from 31.27 ±13.11 to 24.40 ±9.99 μm in R2; p=0.001) were limited to month three.
Researchers determined that significant changes were observed in the thickness of the inner RLs after one year of treatment with IVRs for nAMD. They added that a significant decrease in RPE thickness confined to the first months disappeared at month 12.
SOURCE: Inan, UU Baysal Z, Inan S. Long-term changes in retinal layers in patients undergoing intravitreal ranibizumab for neovascular age-related macular degeneration. Int Ophthalmol 2019; May 8. [Epub ahead of print].
Antidiabetic Drug Metformin Reduces Odds of Developing AMD?
Researchers wrote that studies suggest the antidiabetic drug metformin is associated with decreased risk of several ocular diseases, but no work has investigated the effect of metformin on the development of age-related macular degeneration. They aimed to investigate whether metformin use was associated with a decreased risk of developing AMD.
In this retrospective, case-control study, researchers used medical records from individuals older than 55 who visited a University of Florida health clinic. Three controls were matched for every AMD case—defined by the International Classification of Diseases, Ninth Revision code, based on the Charlson Comorbidity Index—to ensure comparable baseline overall health status. Univariate and conditional multivariable logistic regressions were used to determine the association between a variety of covariates, including metformin use, and AMD diagnosis.
Metformin use was associated with decreased odds of developing AMD, independent of the other covariates investigated (OR, 0.58; CI, 0.43 to 0.79). Other medications assessed weren’t associated with decreased odds of developing AMD.
Though researchers say that individuals who took metformin had decreased odds of developing AMD, they’re quick to add that further research should include clinical trials to investigate prospectively whether metformin actually has a protective effect.
SOURCE: Brown EE, Ball JD, Chen Z, et al. The common antidiabetic drug metformin reduces odds of developing age-related macular degeneration. Invest Ophthalmol Vis Sci. 2019;60:5:1470-7.
Stem Cell-derived RPE in Exudative AMD
Researchers reported on the results of the first case of induced pluripotent stem cell-derived retinal pigment epithelium (iPS-RPE) sheet autologous transplantation using multimodal imaging, as part of a follow-up of a single case.
A patient with exudative age-related macular degeneration and polypoidal choroidal vasculopathy received transplantation of an autologous iPS-RPE cell sheet after removal of a choroidal neovascular membrane in September 2014.
The function of the graft was assessed four years after surgery by color fundus photography, spectral domain-optical coherence tomography, fluorescein angiography, indocyanine green angiography and an adaptive optics retinal camera. Here are some of the findings at the four-year follow-up:
•The transplanted autologous iPS-RPE sheet survived beneath the retina, with slight expansion of the pigmented area and no adverse events.
•The outer nuclear layer above and adjacent to the graft had acceptable thickness and an organized structure.
•FA and SD-OCT suggested the presence of vessel-like structures confined to the grafted area associated with the remaining trunk vessel of preoperative polypoidal choroidal vasculopathy but with no exudative changes.
•Visual acuity was stable, with no additional injections of anti-vascular endothelial growth factor drug.
•The choroidal volume at the graft site was relatively preserved when compared with the volume outside the site without RPE after removal of the choroidal neovascularization.
•ICGA revealed a preserved choriocapillaris around the iPS-RPE sheet.
•Dark, cell-like structures with a predominantly hexagonal arrangement were observed by AO imaging in an area located near the margin of the graft sheet.
•The average inter-cell distance was found to be stable over time.
Researchers wrote that, at four years, the grafted iPS-RPE sheet had survived and appeared to support photoreceptors and choroidal vessels. They added that the morphologic characteristics of the RPE were observed at the transplant site.
SOURCE: Takag S, Mandai M, Gocho K, et al. Evaluation of transplanted autologous induced pluripotent stem cell-derived retinal pigment epithelium in exudative age-related macular degeneration. Ophthalmology Retina 2019; April 26. [Epub ahead of print].
RRD Following Intravitreal Injection of Anti-VEGF
Researchers determined the rate, risk factors and outcomes of rhegmatogenous retinal detachment following intravitreal injection of anti-vascular endothelial growth factor medications, as part of a single-center, retrospective, consecutive review.
Participants included all individuals receiving ranibizumab, bevacizumab or aflibercept for neovascular age-related macular degeneration or retinal vein occlusion between Oct. 1, 2014, and Oct. 1, 2017.
The total number of eyes and injections were determined from billing codes. RRD cases were determined from billing records and confirmed with chart review. Main outcome measures included the rate of retinal detachment and visual acuity outcomes. A total of 180,671 intravitreal injections in 12,718 unique patients were included. Here are some of the findings:
• An RRD occurred in 24 patients within three months following injection, for a rate of one RRD per 7,532 intravitreal injections (0.013 percent) and one RRD per 530 patients (0.19 percent).
• No association was found between post-injection RRD risk and diagnosis (p=0.54), physician experience (p=0.23), injection site (p=0.41), caliper use (p=0.75) or 31- vs. 30-gauge needle use (p=0.18).
• A retinal tear was found in the quadrant of the injection site (within 1.5 clock hours of the injection) in 15 of 24 patients (62.5 percent; p<0.0001).
• At the time of RRD diagnosis, the macula was attached in nine cases (37.5 percent).
• Interventions for RRD repair included pars plana vitrectomy (15 cases), combined scleral buckle-PPV (four cases), pneumatic retinopexy (three cases) and laser/cryotherapy alone (two cases).
• The single-surgery success rate was 54.2 percent with 54.5 percent of recurrent detachments caused by proliferative vitreoretinopathy.
• Average loss from visual acuity recorded at the visit prior to diagnosis of RRD was one line for macula-on detachments vs. 6.8 lines for macula-off detachments (p=0.027) at final follow-up (average 16.3 months).
Researchers concluded that retinal detachment following intravitreal injection was uncommon with a rate of approximately one in 7,500 injections. They added that macular status at the time of RRD diagnosis significantly affected visual outcomes.
SOURCE: Storey PP, Pancholy M, Wibbelsman TD, Obeid A, Su D, Borkar D, Garg S, Gupta O. Rhegmatogenous retinal detachment following intravitreal injection of anti-vascular endothelial growth factor. Ophthalmology. 2019 Apr 28. [Epub ahead of print].
Using OCTA to Monitor Neovascular Regression on Fibrovascular Membrane After Preoperative Intravitreal Conbercept Injection
Researchers quantified the preoperative neovascular change pattern on the fibrovascular membrane in proliferative diabetic retinopathy within seven days after intravitreal injection of conbercept using optical coherence tomography angiography.
In the prospective, observational study of PDR patients with visible fibrovascular membranes (FVMs) receiving or not receiving intravitreal injections of conbercept (IVC), researchers assessed neovascular changes by OCTA pre-IVC and one, three, five and seven days post-IVC. They quantified vessel skeleton density and vessel density (VD) by an intensity-based optical microangiography algorithm. They calculated the interclass correlation coefficient to assess the agreement between measurements, and compared the SD and VD between follow-ups using repeated-measures analysis in the IVC group. Here were some of the findings:
• The ICC was 0.992 (CI, 0.982 to 0.996) for vessel skeleton density, and 0.926 (CI, 0.838 to 0.912) for VD of neovascularization.
• The neovascularization on FVM significantly regressed in the IVC group (n=16) compared with no IVC (n=8) (p=0.001 for vessel skeleton density and p<0.001 for VD).
• The comparisons between consecutive follow-ups showed a statistically significant reduction in vessel skeleton density and VD at one and three days post-IVC; however, from day three onward, the vessel skeleton density and VD remained unchanged.
• No development or progression of tractional retinal detachment was found within the seven-day period after IVC.
Researchers wrote that OCTA-based quantification of the neovascularization on FVM in PDR was feasible, with high inter-reader agreement. They added that regression of neovascularization reached a plateau three days after IVC.
SOURCE: Hu Z, Su Y, Xie P, et al. OCT angiography-based monitoring of neovascular regression on fibrovascular membrane after preoperative intravitreal conbercept injection. Graefes Arch Clin Exp Ophthalmol 2019; May 3. [Epub ahead of print].
OCTA Biomarkers for Predicting Visual Outcomes After Ranibizumab Treatment for DME
Scientists aimed to correlate quantitative optical coherence tomography angiography biomarkers with clinical features, and predict the extent of visual improvement after ranibizumab treatment for diabetic macular edema with OCTA biomarkers, as part of a retrospective longitudinal study conducted in Taiwan.
A total of 50 eyes of 50 individuals with DME, and 22 eyes of 22 healthy individuals except for cataract and refractive error, from one hospital were included.
OCTA (RTVue XR Avanti System, AngioVue version 2017.1) was performed in each eye, and 3×3-mm2 en face OCTA images of the superficial layer and the deep layer were obtained at baseline and after three monthly injections of ranibizumab in the study group. OCTA images were also acquired from the control group.
Scientists comprehensively analyzed five OCTA biomarkers, including foveal avascular zone area (FAZ-A), FAZ contour irregularity (FAZ-CI), average vessel caliber (AVC), vessel tortuosity (VT) and vessel density (VD). They also obtained best-corrected visual acuity and central retinal thickness. In addition, scientists used Student’s T tests to compare OCTA biomarkers between study and control groups, and linear regression models to evaluate correlations between baseline OCTA biomarkers and changes of BCVA/CRT after treatment. Here were some of the findings:
•Eyes with DME had larger AVC, VT, FAZ-A and FAZ-CI, and lower VD than those in the control group (p
<0.001 for all).
•After the loading ranibizumab treatment, OCTA biomarkers improved but didn’t return to normal levels.
•Among all biomarkers, higher inner parafoveal VD in the superficial layer at baseline was the most significantly correlated with visual gain after treatment in the multiple regression model, with adjustment for CRT and ellipsoid zone disruption (p
•To predict visual improvement, outer parafoveal VD in the superficial layer at the baseline had the largest area under the ROC curve (0.787; p
•No baseline OCTA biomarkers had any significant correlation with anatomical improvement.
Scientists found that, for eyes with DME, parafoveal VD in the superficial layer at the baseline was an independent predictor for visual improvement after the loading ranibizumab treatment.
SOURCE: Hsieh Y-T, Alam MN, Le D, et al. Optical coherence tomography angiography biomarkers for predicting visual outcomes after ranibizumab treatment for diabetic macular edema. Ophthalmology Retina 2019; May 6. [Epub ahead of print].
Correlation of Retinal Vascular Perfusion Density with Dark Adaptation in Diabetic Retinopathy
Researchers evaluated the anatomic vs. functional changes in diabetic retinopathy by studying the correlation of retinal vascular perfusion density and dark adaptation.
They performed optical coherence tomography angiography and DA tests in diabetic patients and nondiabetic controls. They also measured DA using the AdaptDx dark adaptometer and recorded the rod intercept (the time for a participant's visual sensitivity to recover after a stimulus of a certain intensity). And they acquired macular OCTA images using the RTVue XR Avanti with AngioVue.
Researchers recruited 86 eyes from 57 individuals with diabetes (19 with no DR, 19 with non-proliferative DR and 19 with proliferative DR who had undergone photocoagulation), and 10 eyes from 10 individuals without diabetes.
Researchers reported a significant decrease in vascular density and a prolonged rod intercept as DR progressed (p<0.01). They found a negative trend between vascular density and the rod intercept; the negative trend in the deep layer (R2=0.28) was more substantial than that in the superficial layer (R2=0.14). Prolonged rod intercept was associated with elevated HbA1c (R2=0.08).
Researchers concluded that vascular density of the macula could be assessed by OCTA, and functional changes in the outer retina could be measured non-invasively by DA. They determined that the severity of vascular density decrease and DA prolongation were proportional to DR progression. Furthermore, they wrote, decreased deep retinal vascular perfusion density and impaired DA response were correlated to (and showed an associated negative trend based on) DR severity.
SOURCE: Hsiao CC, Hsu HM, Yang CM, et al. Correlation of retinal vascular perfusion density with dark adaptation in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2019; Apr 17. [Epub ahead of print].
Association of RVO with Cardiovascular Events and Mortality
Investigators wrote that previous studies examining the association of retinal vein occlusion and cardiovascular events have been inconsistent and have mostly focused on stroke and myocardial infarction. The goal of this study was to use a meta-analysis to examine the available evidence examining the association of RVO with incident cardiovascular events and mortality.
A systematic review and meta-analysis included all longitudinal cohort studies published in PubMed, Embase and the Cochrane Library from inception to April 7, 2018, that: evaluated the association of baseline RVO and incident cardiovascular events and/or mortality; provided multivariate-adjusted risk estimates with 95% confidence intervals; and that had average follow-up ≥1 year. Investigators used the Newcastle-Ottawa scale to assess study quality. Multivariate-adjusted risk estimates with 95% CI along with study characteristics were extracted from each study, and pooled risk ratios (RRs) with 95% CI were generated using a random-effects model with inverse-variance weighting to account for heterogeneity.
Main outcomes were incident stroke (fatal or nonfatal), myocardial infarction, heart failure, peripheral arterial disease, all-cause mortality and cardiovascular mortality. Fifteen cohort studies with a total of 474,466 individuals (60,069 with RVO and 414,397 without RVO) were included. Here were some of the findings:
• Each study had Newcastle-Ottawa scale score ≥6, indicating moderate-to-high quality.
• Retinal vein occlusion was associated with: increased risk of stroke (RR=1.45; CI, 1.31 to 1.60); myocardial infarction (RR=1.26; CI, 1.17 to 1.37); heart failure (RR=1.53; CI, 1.22 to 1.92); peripheral arterial disease (RR=1.26; CI, 1.09 to 1.46); and all-cause mortality (RR=1.36; CI, 1.02 to 1.81), but wasn’t associated with increased risk of cardiovascular mortality (RR=1.78; CI, 0.70 to 4.48).
Investigators found that individuals with RVO had an increased risk of cardiovascular events and all-cause mortality. They wrote that more studies would be needed to determine the highest risk periods for cardiovascular events and mortality after RVO, and whether immediate cardiovascular evaluation and intervention would improve outcomes.
SOURCE: Wu CY, Riangwiwat T, Limpruttidham N, et al. Association of retinal vein occlusion with cardiovascular events and mortality: A systematic review and meta-analysis. Retina 2019; Feb 28. [Epub ahead of print].
Surgical Outcomes of Vitrectomy for Macular Hole Retinal Detachment in Highly Myopic Eyes
Investigators assessed surgical outcomes of macular hole retinal detachment in highly myopic eyes, as part of a multicenter retrospective case study. A total of 110 eyes with retinal detachment due to macular hole were evaluated.
Researchers reviewed the medical records of consecutive patients who underwent vitrectomy between January 2010 and December 2015 to treat MHRD in 10 hospitals of the Japan Clinical Retinal Study Team. The main outcome measures included the retinal re-attachment rate and macular hole closure rate after initial surgery.
Investigators found that the retina was re-attached in 85 percent of eyes, and the macular hole was closed in 52 percent of eyes after initial surgeries. Eyes with gas tamponades achieved a higher re-attachment rate than those with silicone oil tamponades.
Investigators concluded that the gas tamponade group achieved a better retinal reattachment rate than the silicone oil tamponade group. As such, they wrote, gas tamponade could be the first choice for MHRD.
Source: Kakinoki M, Araki T, Iwasaki M, et al. Surgical outcomes of vitrectomy for macular hole retinal detachment in highly myopic eyes: A multicenter study. Ophthalmology Retina 2019; May 3. [Epub ahead of print].
FDA APPROVES EYLEA INJECTION FOR DIABETIC RETINOPATHY
Regeneron Pharmaceuticals announced that the FDA approved the Eylea (aflibercept) injection to treat all stages of diabetic retinopathy. Eylea is the only vascular endothelial growth factor inhibitor approved with two dosing options for DR, enabling doctors to customize treatment to their patients' needs, Regeneron says. In DR, Eylea may be dosed every eight weeks following five initial monthly injections, or every four weeks. Read more.
SOURCE: Regeneron, May 2019
PHASE II BOULEVARD STUDY REVEALS SEVERAL POSITIVE FINDINGS
Roche's and Genentech’s Phase II BOULEVARD study, published in Ophthalmology, showed the investigational molecule, faricimab, was superior to ranibizumab in achieving visual acuity gains for people with diabetic macular edema. Further, the sponsors say that faricimab consistently showed an advantage over ranibizumab in other visual and anatomic outcomes, as well as increased durability, which could potentially mean less frequent treatments for patients. Faricimab is a novel, bispecific antibody that simultaneously binds to and inhibits both vascular endothelial growth factor A and Angiopoietin-2, and is the first bispecific antibody designed specifically for the treatment of retinal eye diseases. The study met its primary endpoint by demonstrating a statistically significant improvement in best-corrected visual acuity in treatment-naïve patients at 24 weeks for faricimab 6 mg versus ranibizumab alone, with an adjusted mean difference of +3.6 letters. Read more.
Source: Roche, Genentech and April 2019
EyePoint Presents Positive Yutiq Phase III Data at ARVO
EyePoint Pharmaceuticals presented 36-month efficacy and safety data supporting the efficacy of the company’s Yutiq (fluocinolone acetonide intravitreal implant) 0.18 mg three-year micro-insert for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. The 36-month follow-up data of the Phase III clinical trial showed a uveitis recurrence rate of 56.3 percent for Yutiq, which was significantly lower than that of sham-treated eyes, which was 92.9 percent. Macular edema was resolved in 85 percent of Yutiq-treated eyes and 70 percent of sham-treated eyes that had edema recorded at baseline. Read more.
SOURCE: EyePoint Pharmaceuticals, May 2019
GENSIGHT ANNOUNCES POSITIVE DATA SAFETY MONITORING BOARD REVIEW AND CONTINUATION OF PIONEER PHASE I/II CLINICAL TRIAL
GenSight Biologics announced that the independent Data Safety Monitoring Board completed its first safety review of the ongoing PIONEER Phase I/II clinical trial of GS030 combining gene therapy and optogenetics for the treatment of retinitis pigmentosa. The DSMB confirmed the absence of any safety issues for the first cohort of three subjects who received a single intravitreal injection of 5e10 vg combined with a wearable optronic visual stimulation device. The DSMB recommended moving forward as planned without any modification in the protocol and recruiting the second cohort of three subjects receiving an escalating dose of 1.5e11 vg. Read more.
SOURCE: GenSight Biologics, May 2019
WATCHFUL WAITING REASONABLE FOR PATIENTS WITH DME AND GOOD VISION
People with good vision, despite having center-involved diabetic macular edema, can safely forgo immediate treatment of their eye condition as long as they are closely monitored and treatment begins promptly if vision worsens, according to clinical trial results in JAMA Ophthalmology. The study was conducted by the DRCR Retina Network. Read more.
SOURCE: NIH, April 2019
2CTECH INITIATES FIRST CLINICAL PROGRAM USING NANOPARTICLES TO TREAT RP
2Ctech initiated a clinical program to demonstrate the effectiveness and safety of Quantum Dots to achieve photovoltaic stimulation of the neural retina for preservation or enhancement of vision in patients with retinal degenerative diseases, in particular retinitis pigmentosa. In previous pre-clinical and first-in-human trials, a one-time injection of QDs was administered into the vitreous and trial outcomes provided strong evidence of safety and positive indications of meaningful vision enhancement, the company claims. Read more.
SOURCE: 2Ctech, April 2019
FDA WARNING: AMEX PHARMACY ISSUES VOLUNTARY NATIONWIDE RECALL FOR LOT OF BEVACIZUMAB SYRINGES
AmEx Pharmacy says it voluntarily recalled “one lot of bevacizumab 1.25mg/0.05mL 31G injectable to the consumer/user level.” The FDA reported that the monoject syringe of this product might become difficult to express, and applying additional force while the needle is in the eye might cause injury to the patient. Read more.
SOURCE: FDA, April 2019
B+L ANNOUNCES UPDATE FROM ARMOR STUDY
Bausch + Lomb announced that the results from nearly 10 years of the Antibiotic Resistance Monitoring in Ocular MicRoorganisms surveillance study (ARMOR) were presented at the ARVO annual meeting in Vancouver. The ARMOR study tracks in vitro antibiotic susceptibility profiles among ocular bacterial pathogens of significance. Researchers also presented preliminary 2018 surveillance data on antibiotic resistance levels. Initiated in 2009, ARMOR is the only ongoing multicenter survey of antibiotic resistance patterns specific to ocular pathogens in the United States, B+L notes. Read more.
SOURCE: Bausch + Lomb, April 2019
FDA ACCEPTS AERIE’S IND APPLICATION FOR SUSTAINED-RELEASE IMPLANT
Aerie Pharmaceuticals announced that the FDA reviewed and accepted its Investigational New Drug Application for AR-13503, a novel multi-kinase (rho-kinase/protein kinase C [ROCK/PKC]) inhibitor sustained-release implant. This allows Aerie to initiate human studies in the treatment of neovascular age-related macular degeneration and diabetic macular edema. The IND was submitted in March 2019, and Aerie expects to initiate a first-in-human clinical study later in the second quarter of 2019. Read more.
Source: Aerie Pharmaceuticals, April 2019
INNOVENT ANNOUNCES FIRST PATIENT DOSED IN PHASE I TRIAL OF ITS WET AMD TREATMENT
Innovent Biologics announced that the first patient was successfully dosed in a Phase I clinical trial of IBI302, a novel recombinant fully human bi-specific fusion protein targeting vascular endothelial growth factor and complement proteins, for the treatment of wet age-related macular degeneration. The open-label, single-center, dose escalation clinical trial will evaluate the safety and tolerability of IBI302 in a single intravitreal injection in patients with wet AMD. Read more.
SOURCE: Innovent Biologics, April 2019
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