Physicochemical and Biological Stability Assessment of SB11 (Ranibizumab Biosimilar) Under Ambient and In-Use Storage for Intravitreal Administration.

INTRODUCTION: SB11 (Byooviz™) is a ranibizumab biosimilar that acts as a vascular endothelial growth factor (VEGF)-A inhibitor. Stability data for unopened SB11 vials at room temperature are limited and no data are available for SB11 withdrawn into syringes (in-use) for intravitreal administration. METHODS: SB11 stability was assessed in two different settings: unopened vials stored at 30 ± 2 °C/65 ± 5% relative humidity (RH) for 2 months, and in-use SB11 withdrawn into syringes stored at 5 ± 3 °C for 98 days and then 25 ± 2 °C/60 ± 5% RH for 24 h. The product was stored in the absence of light, and the experimental design followed International Conference on Harmonization and European Medicines Agency requirements for stability evaluation of biological products. Analysis included visual appearance (color, clarity, and presence of visible particles), pH, protein concentration (A280) and purity (size-exclusion high-pressure liquid chromatography, capillary electrophoresis-sodium dodecyl sulfate, imaged capillary isoelectric focusing), biological activity (VEGF binding and neutralization), and safety (sub-visible particulates). RESULTS: Except for charge variants in unopened vials at room temperature after 1 month by US standards, all results met the stability acceptance criteria (US and EU) for both unopened vials and for in-use SB11. There were no major changes in terms of physicochemical stability, biological activity and sub-visible particulates. CONCLUSION: SB11 was stable for longer periods and at higher temperatures than what is stated in the labels of the reference product (Lucentis) and SB11. The physicochemical properties, biological activity, and sub-visible particulates of SB11 in both tested settings (unopened vials at room temperature and in-use product withdrawn into syringes) were maintained under the described storage periods. This information can help to avoid unnecessary delays in patient treatment without any loss in quality and biological activity, lower the workload of health care providers and reduce costs associated with drug waste.

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material, and Subretinal Pigment Epithelium Disease in Neovascular Age-Related Macular Degeneration.

PURPOSE: To assess longitudinally the effect of anti-vascular endothelial growth factor (VEGF) treatment on ellipsoid zone (EZ) integrity, subretinal hyperreflective material (SHRM), and the sub-retinal pigment epithelium (sub-RPE) compartment in eyes with neovascular age-related macular degeneration (nAMD). DESIGN: Post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, phase 2 study comparing brolucizumab 6 mg with aflibercept 2 mg over 56 weeks. PARTICIPANTS: Participants with treatment-naïve nAMD at the initiation of the trial were included in the analysis. METHODS: Eyes were evaluated with spectral-domain OCT at 4-week intervals in the OSPREY trial (n = 81). Spectral-domain OCT scans collected from each visit were segmented automatically using a proprietary, machine learning-enabled higher-order feature-extraction platform for retinal layer, SHRM, and sub-RPE boundary lines, which were evaluated and corrected as needed by masked trained graders. The current analysis focused only on patients evaluated with the Cirrus (Zeiss) platform (n = 28). MAIN OUTCOME MEASURES: Outcome measures included change from baseline in EZ-RPE (i.e., photoreceptor outer segment) volume, EZ-RPE central subfield thickness (CST), total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume. The correlation between each of these measures and best-corrected visual acuity (BCVA) at each visit was evaluated. RESULTS: EZ-RPE volume and EZ-RPE CST showed significant increases, and total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume showed significant decreases from baseline at each visit from weeks 4 through 56 (P < 0.05 at each visit). Ellipsoid zone integrity measures and SHRM volume correlated significantly with BCVA at most visits (P < 0.05). No significant correlation was found between total sub-RPE volume and BCVA. CONCLUSIONS: EZ integrity, SHRM, and sub-RPE disease features in eyes with nAMD showed improvement as early as week 4 of anti-VEGF treatment. EZ integrity measures and SHRM volume were predictors of visual acuity over the first year of treatment.

Twenty-Four-Month OCTA Assessment in Diabetic Patients Undergoing Fixed-Interval Intravitreal Aflibercept Therapy.

BACKGROUND AND OBJECTIVE: Evaluate capillary perfusion density (CPD) in patients with diabetic macular edema (DME) undergoing fixed intravit-real aflibercept injections (IAI) through 24 months. PATIENTS AND METHODS: Prospective, interventional, single-arm study enrolling 20 patients with persistent DME. Patients received IAI every 4 weeks until DME resolution followed by extension to every 8 weeks. Optical coherence tomography angiography was obtained at baseline, 6, 12, and 24 months. RESULTS: Sixteen of 20 eyes completed the study. Baseline mean central subfield thickness was 420 µm, which improved to 251 µm (P < .001). The mean best-corrected visual acuity (BCVA) improved by 5.5 letters (P = .042). The whole superficial CPD decreased by 5.3% (P = .001) and the deep CPD decreased by 4.4% (P = .009). Better BCVA correlated with less CPD loss within the superficial parafovea (r = +0.66 [0.23, 0.88]; P = .006) and whole (r = +0.60 [0.12, 0.85]; P = .017) areas. CONCLUSION: Superficial and deep CPD decreased despite fixed IAI through 24 months. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:448-455.].

Comparative Assessment of Widefield Fundus Autofluorescence Patterns in Retinoschisis and Retinal Detachment.

Purpose: This article characterizes widefield fundus autofluorescence (WF-FAF) patterns in retinoschisis (RS), retinal detachment (RD), and combined retinoschisis-detachment (RS/RD), and to correlate them with spectral-domain optical coherence tomography (SD-OCT) findings. Methods: A retrospective case series of 13 eyes with senile RS, RD, or RS/RD is presented. One eye underwent imaging of 2 areas within the retina, resulting in 14 data points. Independent, masked graders classified pathology on SD-OCT as RS, RD, or RS/RD and graded WF-FAF images for either hypoautofluorescent areas or mixed autofluorescence (AF) (hyper-AF, iso-AF, hyper-AF with hypo-AF, hyper-AF with iso-AF, or hypo-AF with iso-AF). Results: There was no statistically significant correlation between the autofluorescence pattern and the type of retinal abnormality (P = .74). Conclusions: High variability was found in the characterization of WF-FAF in patients with RS and RD. SD-OCT remains the criterion-standard imaging modality in distinguishing RS from RD in clinically ambiguous cases.

Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.

PURPOSE: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study. DESIGN: A post hoc subanalysis of a phase III, prospective clinical trial. PARTICIPANTS: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8). METHODS: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point. MAIN OUTCOME MEASURES: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA). RESULTS: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 µm to 31.6 µm, P < 0.001; 2q8: 25.2 µm to 31.4 µm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits. CONCLUSIONS: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.

Budget impact analysis of ocriplasmin for the treatment of symptomatic vitreomacular adhesion in the USA.

BACKGROUND: Vitreomacular traction (VMT) treatment options include watchful waiting, vitrectomy and intravitreal ocriplasmin injection (Jetrea®). This analysis used results from the recently completed OASIS randomized clinical trial to evaluate the 2-year budget impact of ocriplasmin injection availability for treatment of Stage I or II VMT without epiretinal membrane formation in a modeled US health plan. MATERIALS & METHODS: VMT prevalence, treatment patterns and disease resolution rates were from literature, a US retinal-specialist survey and the OASIS trial. Medicare payment rates were applied and a national scenario analysis was conducted. RESULTS: With ocriplasmin available, vitrectomy use and complications-related costs decreased. Budget impact of ocriplasmin to the health plan was US$143,599 over 2 years or US$0.0060 per-member per-month. CONCLUSION: Ocriplasmin was projected to be minimally cost-additive at US$0.0060 per-member per-month over 2 years.

Assessment of inner and outer retinal layer metrics on the Cirrus HD-OCT Platform in normal eyes.

PURPOSE: Ellipsoid zone (EZ) and outer retinal integrity are strongly linked to visual prognosis, but quantitative normative data is lacking. This study evaluates the EZ, outer retina, and inner retina in eyes without macular disease across a wide age spectrum. METHODS: An IRB-approved study was performed for eyes without macular pathology undergoing Spectral Domain Optical Coherence Tomography (SD-OCT) scans on the Cirrus HD-OCT system (Carl Zeiss Meditec, Oberkochen, Germany). Scans were analyzed using a previously described automated EZ mapping tool with line-by-line manual verification. Segmentation included internal limiting membrane (ILM), outer nuclear layer/Henle fiber layer complex (ONL/HFL), EZ, and the retinal pigment epithelium (RPE). The output included metrics for the inner retina (ILM-OPL/HFL), outer retina (ONL/HFL-RPE), EZ-RPE area and volume, and en face EZ mapping. EZ-RPE attenuation on en face mapping was defined as EZ-RPE thickness < 20 um, and total attenuation was 0 um. Imaging parameters were assessed for the group and compared to age, sex, visual acuity and spherical equivalent. RESULTS: 167 eyes from 167 subjects were included. Mean age was 49.7 years (range 10-84 years). The mean foveal retinal thickness was 200.58 ± 19.22 um. Mean inner retinal thickness was 21.47 ± 13.60 um. Mean outer retinal thickness was 179.11 ± 18.52 um. Mean EZ-RPE thickness was 50.58 ± 6.01um. The mean EZ-RPE volume was 1.20 ± 0.10 mm3. Mean EZ attenuation percentage per macular map area was 0.87% ± 1.13% and mean percentage total attenuation was 0.12% ± 0.14%. Total and inner retinal thickness metrics decreased with age. Mean outer retinal thickness increased with age. EZ-RPE parameters were unchanged with age. However, EZ attenuation was negatively correlated with age. CONCLUSION: This study provides important information for inner and outer retinal parameters. Future research on quantitative EZ integrity can utilize this data for comparison.

The DISCOVER Study 3-Year Results: Feasibility and Usefulness of Microscope-Integrated Intraoperative OCT during Ophthalmic Surgery.

PURPOSE: To report the 3-year assessment of feasibility and usefulness of microscope-integrated intraoperative OCT (iOCT) during ophthalmic surgery. DESIGN: Prospective, consecutive case series. PARTICIPANTS: Adult participants undergoing incisional ophthalmic surgery with iOCT imaging who consented to be enrolled in the Determination of Feasibility of Intraoperative Spectral-Domain Microscope Combined/Integrated OCT Visualization during En Face Retinal and Ophthalmic Surgery (DISCOVER) study. METHODS: The DISCOVER study is a single-site, multisurgeon, institutional review board-approved investigational device prospective study. Participants included patients undergoing anterior or posterior segment surgery who underwent iOCT imaging with 1 of 3 prototype microscope-integrated iOCT systems (i.e., Zeiss Rescan 700, Leica EnFocus, or Cole Eye iOCT systems). Clinical characteristics were documented, iOCT was directed by the operating surgeon at predetermined surgical time points, and each surgeon completed a questionnaire after surgery to evaluate the usefulness of iOCT during surgery. MAIN OUTCOME MEASURES: Feasibility of iOCT based ability to obtain an OCT image during surgery and usefulness of iOCT based on surgeon reporting during surgery. RESULTS: Eight hundred thirty-seven eyes (244 anterior segment cases and 593 posterior segment cases) were enrolled in the DISCOVER study. Intraoperative OCT demonstrated feasibility with successful image acquisition in 820 eyes (98.0%; 95% confidence interval [CI], 96.8%-98.8%). In 106 anterior segment cases (43.4%; 95% CI, 37.1%-49.9%), the surgeons indicated that the iOCT information impacted their surgical decision making and altered the procedure. In posterior segment procedures, surgeons reported that iOCT enabled altered surgical decision making during the procedure in 173 cases (29.2%; 95% CI, 25.5%-33.0%). CONCLUSIONS: The DISCOVER iOCT study demonstrated both generalized feasibility and usefulness based on the surgeon-reported impact on surgical decision making. This large-scale study confirmed similar findings from other studies on the potential value and impact of iOCT on ophthalmic surgery.

Long-Term Assessment of Macular Atrophy in Patients with Age-Related Macular Degeneration Receiving Anti-Vascular Endothelial Growth Factor.

PURPOSE: Although intravitreal anti-vascular endothelial growth factor (VEGF) injection has become the mainstay treatment for neovascular age-related macular degeneration (nAMD), emerging studies suggest that anti-VEGF may be correlated with the development of macular atrophy (MA) in chronic therapy. The purpose of the current study is to determine the prevalence and progression of MA in nAMD treated with chronic anti-VEGF in a routine clinical practice. DESIGN: Retrospective cohort. PARTICIPANTS: Patients with nAMD who were previously treatment-naïve and treated with anti-VEGF at the Cole Eye Institute for at least 4 years. METHODS: This is chart review on anti-VEGF treated patients with nAMD with baseline and yearly follow-up spectral domain-OCT for at least 4 years. Retinal pigment epithelium subillumination analysis was used to automate identification of atrophy. Segmentation errors were manually corrected by 4 expert raters using a standardized grading protocol to quantify MA size. Patient baseline characteristics and treatment course were analyzed to identify predictive factors for the development of MA. MAIN OUTCOME MEASURES: MA growth rate and prevalence in cohorts with and without baseline atrophy. RESULTS: A total of 79 eyes from 66 patients (79.8±7.4 years, 63% were female) with nAMD and 4 years of follow-up with anti-VEGF injections were identified. The mean baseline visual acuity was 0.48±0.25 logarithm of the minimum angle of resolution (20/60 Snellen equivalent), and the mean final visual acuity was 0.48±0.49 logarithm of the minimum angle of resolution (20/44 Snellen equivalent, P = 0.23). The average number of injections was 19.8±9.8. MA was observed in 12.7% of eyes at baseline with an average annual growth rate of 0.7±0.5 mm2. In eyes without baseline MA, atrophy developed in 53.6% eyes by year 4 with a growth rate of 0.2±0.4 mm2 per year. Multiple linear regression analysis revealed that the progression of MA was positively correlated with age (R = 0.02, P = 0.009). CONCLUSIONS: More than half of patients with nAMD treated with anti-VEGF injections for 4 years developed new MA. Atrophy progression was most strongly correlated with age, which suggests that baseline disease characteristics may be more predictive of MA progression than cumulative anti-VEGF treatment.

Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17,979 per QALY (€15,773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone.

Factors associated with persistent subfoveal fluid and complete macular hole closure in the PIONEER study.

PURPOSE: To investigate preoperative and intraoperative factors associated with persistent subfoveal fluid in surgically closed macular holes (MHs). METHODS: This was a prospective consecutive case series of eyes undergoing surgical repair for full-thickness MH in the PIONEER study, a prospective intraoperative optical coherence tomography (OCT) multisurgeon single-center study. Thirty-seven eyes (36 patients) with surgically closed MH were studied. Quantitative OCT analysis was performed including intraoperative MH area, volume, ellipsoid zone to retinal pigment epithelium (EZ-RPE) height, extent of subretinal hyporeflectivity (SRHR), and the amount of postoperative subfoveal fluid. RESULTS: Persistent subfoveal fluid was identified in 58% of eyes at 2 weeks following surgery. The mean time to two-line improvement in visual acuity was greater in eyes with persistent subfoveal fluid (P = 0.03). Final visual acuity did not correlate with the initial presence of fluid. Two intraoperative factors following internal limiting membrane (ILM) peeling were associated with the formation of persistent subfoveal fluid: EZ-RPE height and SRHR width (P < 0.01). These were both negatively correlated with amount of postoperative subfoveal fluid (P = 0.028 and 0.04, respectively). CONCLUSIONS: Persistent subfoveal fluid following MH surgery is a common finding that appears to delay visual recovery but not effect final visual outcome. The incidence of persistent subfoveal fluid appears to be related to intraoperative alterations after ILM peeling in the outer retinal architecture (e.g., increased EZ-RPE height and SRHR width). This finding suggests a novel mechanism for facilitating MH closure through ILM peeling (e.g., altering photoreceptor/RPE adherence and increasing retinal mobility that allows for complete hole closure).

Intrasurgical dynamics of macular hole surgery: an assessment of surgery-induced ultrastructural alterations with intraoperative optical coherence tomography.

PURPOSE: To evaluate the intrasurgical retinal architectural and macular hole (MH) geometric alterations that occur during surgical MH repair using intraoperative optical coherence tomography. METHODS: A retrospective, multisurgeon, single-center, consecutive case series of 21 eyes undergoing surgical repair for MH with concurrent intraoperative optical coherence tomography using a custom microscope-mounted optical coherence tomography system was performed. All patients underwent surgical repair with pars plana vitrectomy, membrane peel, and gas tamponade. A novel three-dimensional segmentation algorithm was used for volumetric analysis of intrasurgical changes of MH geometry after surgical repair. Intraoperative optical coherence tomographic characteristics analyzed included MH volume, minimum diameter, base area, and hole height. Outer retinal architecture changes were analyzed both quantitatively and qualitatively. RESULTS: All 21 eyes were successfully imaged with intraoperative optical coherence tomography. Nineteen of 21 eyes had images of sufficient signal strength to allow for quantitative analysis. Significant changes were noted in MH geometry after internal limiting membrane peeling including increased MH volume, increased base area, and decreased top area (all P < 0.03). Additionally, increased subretinal hyporeflectance was noted by expansion of the height between the inner segment/outer segment and retinal pigment epithelium bands (P = 0.008). Peeling methods and surgeon experience did not correlate with the magnitude of architectural alterations. Macular hole algorithm measurements and alterations were associated with visual outcome and MH closure. CONCLUSION: Significant alterations occur in MH geometry and outer retinal structure after internal limiting membrane peeling. These changes are subclinical and unable to be appreciated with en face surgical microscope viewing and require intraoperative optical coherence tomography for visualization. Preliminary analysis of these measurements identified an association with visual outcome and successful MH closure. The functional significance of these changes deserves further study.

Novel microarchitectural dynamics in rhegmatogenous retinal detachments identified with intraoperative optical coherence tomography.

PURPOSE: To evaluate ultrastructural macular changes during rhegmatogenous retinal detachment repair using intraoperative optical coherence tomography (iOCT). METHODS: A multisurgeon, single-center consecutive case series of 9 eyes undergoing surgical repair for macula-involving rhegmatogenous retinal detachment with iOCT imaging using a custom microscope-mounted spectral domain OCT system. All patients underwent combined vitrectomy/scleral buckle repair. Imaging characteristics were analyzed, including persistence of subclinical intraoperative subretinal fluid and architectural changes associated with intraoperative maneuvers. Clinical characteristics were analyzed. RESULTS: Nine eyes of nine patients were identified that underwent iOCT imaging during macula-involving rhegmatogenous retinal detachment repair. Persistent subclinical subretinal fluid was identified in 100% of eyes after perfluoro-n-octane instillation. Significant alterations to the foveal architecture were detected with iOCT in 100% of cases. Three foveal configurations were noted based on iOCT findings. Stage 1 was characterized by a small area of subfoveal hyporeflectivity (3/9 eyes), Stage 2 had prominent subretinal hyporeflectivity and foveal thinning with indeterminate macular hole (MH) formation (3/9 eyes), and Stage 3 demonstrated definitive full-thickness MH (3/9 eyes). No eyes were noted to have a MH preoperatively or in the immediate postoperative period. One Stage 3 eye developed a full-thickness MH 7 months postoperatively. Stage 3 configuration was associated with poorer final postoperative visual acuity (P = 0.009). CONCLUSION: Microarchitectural changes occur during intraoperative repair of retinal detachments, including significant alterations in foveal configuration and persistent subretinal fluid. These features may help to prognosticate outcomes. These findings also suggest a possible novel mechanism for postrhegmatogenous retinal detachment MH formation.

Prospective evaluation of visual acuity assessment: a comparison of snellen versus ETDRS charts in clinical practice (An AOS Thesis).

THE PURPOSE OF THIS STUDY WAS TWOFOLD: first, to prospectively compare visual acuity (VA) scores obtained with Snellen charts versus Early Treatment Diabetic Retinopathy Study (ETDRS) charts in a "real world" retinal practice, and second, to see if there was a difference in visual acuity measurements obtained with ETDRS charts starting at 4 or 2 meters. METHODS: Prospective, consecutive evaluation of patients who underwent best-corrected visual acuity testing of their right eye performed at a single seating by the same experienced, certified vision examiner in the same room with standardized low light conditions using a projected Snellen chart at 20 feet, and two different back-illuminated ETDRS charts placed 4 and 2 meters from the patient. RESULTS: One hundred sixty-three eyes were included in the study. The mean Snellen VA was 0.67 logMAR (20/94), ETDRS VA at 4 meters was 0.54 logMAR (~20/69), and ETDRS VA at 2 meters was 0.51 logMAR (~20/65). The mean difference was 6.5 letters better on the ETDRS chart (P=.000000001). As the VA worsened, there was increased variability between the charts and the mean discrepancy between charts also increased. Subgroup analysis revealed the greatest difference between charts was in the poor vision subgroup (<20/200) with a difference of 0.2 logMAR (10 letters; P=.0000002). Patients with exudative age-related macular degeneration (AMD) had the greatest disparity on vision testing, but patients with dry AMD and diabetic retinopathy also exhibited significant differences. CONCLUSIONS: Visual acuity scores were significantly better on ETDRS charts compared to Snellen charts. The difference was greatest with poor visual acuity (<20/200) and in patients with exudative AMD. Thus, caution should be exercised when comparing data using the different charts.