Publications by authors named "Charles C Wykoff"

158 Publications

Early Residual Fluid-free Status and Long-term BCVA outcomes: A Treatment Agnostic, Post-hoc Analysis of Pooled HAWK and HARRIER Data.

Am J Ophthalmol 2021 Oct 22. Epub 2021 Oct 22.

Medical Center Ophthalmology Associates, University of Texas Health Center, San Antonio, TX, US. Electronic address:

Purpose: Determine associations between early residual fluid (ERF)-free status and improved long-term visual outcomes.

Design: Clinical cohort study from post hoc analysis of two phase 3 clinical trials' data.

Methods: Independent of treatment allocation, patients from the multicenter, prospective, randomized, double-masked HAWK and HARRIER trials who received either brolucizumab 6 mg or aflibercept 2 mg were split into two cohorts dependent on presence or absence of ERF at week 12. Additionally, similar analyses were performed on presence or absence of early residual intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12. The two groups, ERF-free (N=1051) and ERF (N=366) were compared. Changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST) were determined.

Results: From week 12 to 96, patients who were ERF-free had greater least square (LS) mean increases from baseline for BCVA and CST compared to ERF patients. Greater LS mean differences in BCVA from week 12 to 96 were noted between ERF-free and ERF patients. A greater proportion of patients in the ERF-free cohort reported a ≥5, ≥10, or ≥15 letter improvement and a higher proportion reported BCVA ≥70 letters from baseline to week 96 compared to those with fluid.

Conclusions: Improvements in visual outcomes in ERF-free patients were greater than in ERF patients occurring as early as 4 weeks (week 12) following the last loading dose and continued to week 96. Therefore, ERF status may be a useful indicator of anti-vascular endothelial growth factor treatment response.
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http://dx.doi.org/10.1016/j.ajo.2021.10.017DOI Listing
October 2021

Real-Time Diabetic Retinopathy Severity Score Level versus Ultra-Widefield Leakage Index-Guided Management of Diabetic Retinopathy: Two-Year Outcomes from the Randomized PRIME Trial.

J Pers Med 2021 Sep 4;11(9). Epub 2021 Sep 4.

Retina Consultants of Texas, Retina Consultants of America, Houston, TX 77030, USA.

The prospective PRIME trial applied real-time, objective imaging biomarkers to determine individualized retreatment needs with intravitreal aflibercept injections (IAI) among eyes with diabetic retinopathy (DR). 40 eyes with nonproliferative or proliferative DR without diabetic macular edema received monthly IAI until a DR severity scale (DRSS) level improvement of ≥2 steps was achieved. Eyes were randomized 1:1 to DRSS- or PLI- guided management. At the final 2-year visit, DRSS level was stable or improved compared to baseline in all eyes, and mean PLI decreased by 11% ( = 0.73) and 23.6% ( = 0.25) in the DRSS- and PLI-guided arms. In both arms, the percent of (PRN) visits requiring IAI was significantly higher in year 2 versus 1 ( < 0.0001). The percent of PRN visits receiving IAI during year 1 was significantly correlated with the percent of PRN visits with IAI during year 2 ( < 0.0001). Through week 104, 77.4% of instances of DRSS level worsening in the DRSS-guided arm were preceded by or occurred alongside an increase of PLI. Overall, consistent IAI re-treatment interval requirements were observed longitudinally among individual patients. Additionally, PLI increases appeared to precede DRSS level worsening, highlighting PLI as a valuable biomarker in the management of DR.
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http://dx.doi.org/10.3390/jpm11090885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465170PMC
September 2021

Morphological characteristics of eyes with neovascular age-related macular degeneration and good long-term visual outcomes after anti-VEGF therapy.

Br J Ophthalmol 2021 Sep 24. Epub 2021 Sep 24.

Doheny Eye Institute, Doheny Image Reading Center, Los Angeles, California, USA

Purpose: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy.

Methods: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands.

Results: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 μm) compared with the intermediate (86.25 μm) or good (97.92 μm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 μm) compared with eyes with intermediate vision (64.37 μm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 μm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001).

Conclusion: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment.
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http://dx.doi.org/10.1136/bjophthalmol-2021-319602DOI Listing
September 2021

Inhibition of Complement C3 in Geographic Atrophy with NGM621: Phase 1 Dose-Escalation Study Results.

Am J Ophthalmol 2021 Sep 9. Epub 2021 Sep 9.

NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080.

Purpose: To evaluate the safety and tolerability of single and multiple intravitreal injections of NGM621 in patients with geographic atrophy (GA) and to characterize the pharmacokinetics and immunogenic potential.

Design: Multicenter, open-label, single- and multiple-dose phase 1 study.

Methods: Fifteen patients enrolled at 4 sites in the United States. Participants had GA secondary to age-related macular degeneration, lesion size ≥2.5 mm and best-corrected visual acuity of 4 to 54 letters (20/80 to 20/800 Snellen equivalent) in the study eye and no history of choroidal neovascularization in either eye. Patients who met eligibility criteria were treated in a single ascending-dose phase (2 mg, 7.5 mg, 15 mg) or received 2 doses NGM621 15 mg 4 weeks apart in the multidose phase and were followed for 12 weeks (85 days). Assessments included adverse events, best-corrected visual acuity, low luminance visual acuity, vital signs, clinical laboratory evaluations, GA lesion area as measured by fundus autofluorescence, spectral domain optical coherence tomography, and pharmacokinetic, immunogenicity, and pharmacodynamic assessments.

Results: All 15 participants completed the 12-week study. There were no serious adverse events and no drug-related adverse events, and no choroidal neovascularization developed in either eye. Mean visual acuity and GA lesion area appeared stable through week 12 for all cohorts. Pharmacokinetic analyses indicated that NGM621 serum exposures appeared to be dose proportional, and no antidrug antibodies were identified at any of the evaluated time points.

Conclusions: In this small, open-labelled, 12-week phase 1 study, NGM621 was safe and tolerable when administered intravitreally up to 15 mg.
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http://dx.doi.org/10.1016/j.ajo.2021.08.018DOI Listing
September 2021

Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy: Results From the PANORAMA Randomized Clinical Trial.

JAMA Ophthalmol 2021 Sep;139(9):946-955

Regeneron Pharmaceuticals, Tarrytown, New York.

Importance: Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications.

Objective: To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME).

Design, Setting, And Participants: The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better.

Interventions: Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group).

Main Outcomes And Measures: Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100.

Results: Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified.

Conclusions And Relevance: In this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence.

Trial Registration: ClinicalTrials.gov Identifier: NCT02718326.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.2809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343518PMC
September 2021

Expanded Clinical Spectrum of Pentosan Polysulfate Maculopathy: A Macula Society Collaborative Study.

Ophthalmol Retina 2021 Jul 21. Epub 2021 Jul 21.

Kellogg Eye Institute, University of Michigan, Ann Arbor, Michigan.

Purpose: Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings.

Design: Multi-institutional retrospective study.

Participants: Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4, 2020.

Methods: Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics.

Main Outcome Measures: Pentosan polysulfate exposure characteristics and fundus imaging features.

Results: There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2-18.9), with a median cumulative exposure of 1.5 kg (0.9-2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients.

Conclusions: Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.
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http://dx.doi.org/10.1016/j.oret.2021.07.004DOI Listing
July 2021

Rationale for American Society of Retina Specialists Best Practice Recommendations for Conducting Vitreoretinal Surgery during the COVID-19 Era.

J Vitreoretin Dis 2020 Oct 27;4(5):420-429. Epub 2020 Jul 27.

Murray Ocular Oncology and Retina, Miami FL.

Purpose: To detail the rationale behind recommendations recently published by the American Society of Retina Specialists (ASRS) outlining best practices for safety of vitreoretinal surgeons and staff while performing vitreoretinal surgery during the coronavirus disease (COVID)-19 pandemic.

Methods: The committee for ASRS Best Practices for Retinal Surgery during the COVID-19 Pandemic reviewed existing evidence and information on SARS-CoV-2 transmission, and risk factors during vitreoretinal surgery. Recommendations were based on best available published data, cumulative clinical experiences, and recommendations and policies from other organizations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of recommendations and confidence in the evidence. These serve as interim recommendations which are routinely updated given gaps of knowledge and lack of high-quality data on this evolving subject.

Results: Relevant existing literature related to methods of transmission, and ocular manifestations of SARS-CoV-2 are summarized. The data and clinical experiences driving recommendations for pre-operative, intraoperative and post-operative surgical considerations, anesthesia choice, as well as considerations for intravitreal injections are provided.

Conclusion: Recommendations are provided with the goal of protecting vitreoretinal surgeons and associated personnel from exposure to SARS-CoV-2 during interventional vitreoretinal procedures. This is a rapidly evolving topic with numerous remaining gaps in our current knowledge. As such, recommendations will evolve and the current manuscript is intended to serve as a foundation for continued dialogue on best practices.
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http://dx.doi.org/10.1177/2474126420941707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247449PMC
October 2020

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

Br J Ophthalmol 2021 Jun 7. Epub 2021 Jun 7.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA

Background: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME).

Methods: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response.

Results: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05).

Conclusions: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318726DOI Listing
June 2021

Brolucizumab vs aflibercept and ranibizumab for neovascular age-related macular degeneration: a cost-effectiveness analysis.

J Manag Care Spec Pharm 2021 Jun;27(6):743-752

Retina Consultants of Houston, Retina Consultants of America, and Blanton Eye Institute and Houston Methodist Hospital, Houston, TX.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide and is the most common cause of blindness in developed countries. Despite antivascular endothelial growth factor (anti-VEGF) therapy demonstrating improvements in visual and anatomical outcomes, unmet needs remain. Brolucizumab-dbll (ie, brolucizumab), a VEGF inhibitor for treatment of neovascular (wet) AMD and recently approved by the FDA for its treatment of wet AMD, attempts to mitigate treatment burden through less frequent injections. To assess the incremental cost-effectiveness of brolucizumab compared with aflibercept and ranibizumab, given similar costs per injection and the potential for longer dosing intervals based on phase 3 clinical trial data. A Markov model was developed to model the treatment of wet AMD patients with brolucizumab vs aflibercept and vs ranibizumab over a lifetime time horizon (base case) and 5-year time horizon (scenario analysis). The Markov model consisted of 3 primary health states: on treatment, off treatment, and death. Markov substates (5 total) described visual acuity (VA) ranging from no vision impairment to blindness. These VA-based substates were defined by best-corrected visual acuity (BCVA) values measured using Early Treatment Diabetic Retinopathy Study letters. Fixed-dosing regimens for each therapy were included in the model: dosing every 4 weeks (q4w) for the first 3 months followed by dosing q8w/q12w for brolucizumab, dosing q4w for the first 3 months followed by dosing q8w for aflibercept, and q4w for ranibizumab. In the base case, brolucizumab was less costly than aflibercept ($63,614 vs $72,189), and brolucizumab generated 0.0079 more quality-adjusted life-years (QALYs) than aflibercept (4.580 vs 4.572). Lower total costs with brolucizumab were driven by reduced drug costs ($56,432 vs $64,057), reduced administration costs ($6,013 vs $6,825), and reduced monitoring costs ($1,168 vs $1,306). When evaluating the cost-effectiveness of brolucizumab over a 5-year time horizon, brolucizumab was less costly than aflibercept ($44,644 vs $50,772) and generated an additional 0.0049 QALYs (2.953 vs 2.948). Additionally, brolucizumab was less costly than ranibizumab ($63,614 vs $128,163) and generated 0.0078 more QALYs than ranibizumab (4.580 vs 4.572) in the base case. Lower total costs with brolucizumab were driven by reduced drug costs ($56,432 vs $114,516), reduced administration costs ($6,013 vs $11,541), and reduced monitoring costs ($1,168 vs $2,107). When evaluating the cost-effectiveness of brolucizumab over a 5-year time horizon, brolucizumab was less costly than ranibizumab ($44,644 vs $89,665), and brolucizumab generated an additional 0.0046 QALYs (2.953 vs 2.948). Brolucizumab can be cost saving and cost-effective compared with aflibercept and ranibizumab in the treatment of wet AMD. : Novartis Pharmaceuticals Corporation provided funding to Xcenda for the cost-effectiveness analysis and preparation of this manuscript. Carlton is an employee of Xcenda. Agashivala is employed by Novartis Pharmaceuticals Corporation; Yu was an employee of Novartis Pharmaceutical Corporation at the time of this study. Hassan reports personal fees from iOPEN, BVI/Visitrec, ArcticDx, Bayer, F. Hoffmann-La Roche Ltd, Broadspot, BMC, Katalyst Surgical, Alcon, Vitreq, Surgicube, personal Ocugenix, Regeneron, Allergan, Oculus Surgical, Novartis, Genentech, and Eyepoint, unrelated to this work. Wykoff reports personal fees from Corcept Therapeutics, DORC, EyePoint, Gyroscope, IVERIC Bio, Merck, Notal Vision, ONL Therapeutics, Oxurion, Palatin, PolyPhotonix, Takeda, Thea Open Innovation; grants from Aerie Pharmaceuticals, Aldeyra, Gemini Therapeutics, Graybug Vision, IONIS Pharmaceutical, LMRI, Mylan, Neurotech Pharmaceuticals, Outlook Pharmaceuticals, Samsung Bioepis, Senju, Taiwan Liposome Company, Xbrane BioPharma, Santen; and grants and personal fees from Adverum, Allergan, Apellis, Chengdu Kanghong Biotechnologies (KHB), Clearside Biomedical, Genentech, Kodiak Sciences, NGM Biopharmaceuticals, Novartis, Opthea, Recens Medical, Regenxbio, Roche, and Regeneron, unrelated to this work. This research was presented as a virtual poster at the AMCP 2020 Annual Meeting, April 2020.
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http://dx.doi.org/10.18553/jmcp.2021.27.6.743DOI Listing
June 2021

RETINAL FLUID AND THICKNESS AS MEASURES OF DISEASE ACTIVITY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

Retina 2021 Aug;41(8):1579-1586

Novartis Pharmaceuticals, East Hanover, New Jersey.

Purpose: Retinal fluid and thickness are important anatomical features of disease activity in neovascular age-related macular degeneration, as evidenced by clinical trials that have used these features for inclusion criteria, retreatment criteria, and outcome measures of the efficacy of intravitreal injections of anti-vascular endothelial growth factor agents.

Methods: A literature review of anatomical measures of disease activity was conducted.

Results: Treatment goals for neovascular age-related macular degeneration include improving/maintaining vision by drying the retina, and several analyses have evaluated the relationship between visual function and anatomy. The change in retinal thickness has been found to correlate with the change in the visual acuity, and variation in retinal thickness may predict visual acuity outcomes. In addition, specific fluid compartments may have different prognostic values. For example, the presence of intraretinal fluid has been associated with poorer visual acuity, whereas the presence of subretinal fluid has been associated with better visual acuity. Retinal fluid and thickness are important for selecting dosing interval durations in clinical trials and clinical practice.

Conclusion: Retinal thickness and retinal fluid are common anatomical measures of disease activity in neovascular age-related macular degeneration. Further research is required to fully elucidate the relationship between anatomical features and visual outcomes in neovascular age-related macular degeneration.
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http://dx.doi.org/10.1097/IAE.0000000000003194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297539PMC
August 2021

Investigational Agents in Development for the Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

BioDrugs 2021 May 24;35(3):303-323. Epub 2021 Apr 24.

Retina Consultants of Texas, Retina Consultants of America, 4460 Bissonnet St., Suite 200, Bellaire, Texas, 77401, United States.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration, a late-onset, complex, genetic degenerative disease of the retina. Multiple environmental and genetic factors have been implicated in the development of GA, a pathology ultimately defined by loss of photoreceptors and the underlying retinal pigment epithelium and choriocapillaris. The personal burden of GA has been documented to have a substantial negative impact on quality of life, with progressive and cumulative loss of visual function each year. Currently, there are no treatments to prevent or slow the development or progression of GA. Multiple genetic and histopathologic studies have implicated dysregulation of the complement cascade in GA pathogenesis, leading to the development of several investigational pharmaceuticals targeting key factors in this inflammatory pathway. Several other biochemical pathways have also been implicated in GA development and progression, such as mitochondrial components, mediators of apoptosis and molecules involved in extracellular matrix remodeling, many of which are also being investigated for their potential value as therapeutic targets for GA treatment. Recent advancements in our understanding of GA pathogenesis and the progression of multiple potential therapeutics into later-stage human clinical trials hold great promise for a clinically effective therapeutic for patients with GA to emerge within the near future.
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http://dx.doi.org/10.1007/s40259-021-00481-yDOI Listing
May 2021

Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial.

JAMA Ophthalmol 2021 May;139(5):542-547

Retina Vitreous Associates Medical Group, Los Angeles, California.

Importance: Anti-vascular endothelial growth factor (VEGF) agents may provide a prophylactic effect in high-risk eyes with intermediate dry age-related macular degeneration (AMD) against conversion to exudative AMD (eAMD), lowering the risk of vision loss.

Objective: To evaluate intravitreal aflibercept injection (IAI) as prophylaxis against the conversion to eAMD in high-risk eyes at 24 months.

Design, Setting, And Participants: This single-masked, sham-controlled, randomized clinical trial performed at 4 US clinical sites enrolled patients with intermediate AMD in 1 eye (study eye), defined as presence of more than 10 medium drusen (≥63 to <125 μm), at least 1 large druse (≥125 μm), and/or retinal pigmentary changes, and eAMD in the fellow eye. Patients were treated from June 23, 2015, to March 13, 2019.

Interventions: Intravitreal aflibercept injection (2 mg) or sham quarterly injection for 24 months (1:1 randomization).

Main Outcomes And Measures: The primary end point was the proportion of patients with conversion to eAMD at month 24 characterized by development of choroidal neovascularization, as assessed by leakage on fluorescein angiography and fluid on spectral-domain optical coherence tomography by an independent masked reading center.

Results: Of 128 patients enrolled, 127 (63 in the IAI group and 64 in the sham group) were included in the primary analysis (68 men [53.5%]; mean [SD] age, 76.5 [8.1] years). Baseline demographic and clinical characteristics were balanced between the groups. By month 24, 6 patients (9.5%) in the IAI group and 7 (10.9%) in the sham group developed eAMD (P = .98). Patients with a history of eAMD for longer than 2 years in their fellow eye at baseline showed a lower rate of conversion to eAMD in the study eye compared with those with a history of eAMD for 2 years or less in the fellow eye. Safety was consistent with previous studies involving intravitreal anti-VEGF injections.

Conclusions And Relevance: In this evaluation of quarterly anti-VEGF exposure as prophylaxis to reduce conversion of eyes with high-risk dry AMD to eAMD, the rates of conversion were not lower in the IAI group compared with the sham treatment group at month 24. Understanding the mechanism of conversion to eAMD and therapies that could prevent this event remains an important unmet need.

Trial Registration: ClinicalTrials.gov Identifier: NCT02462889.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974836PMC
May 2021

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

Ophthalmology 2021 Sep 10;128(9):1325-1336. Epub 2021 Mar 10.

Apellis Pharmaceuticals, Leominster, Massachusetts.

Objectives: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.

Design: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).

Subjects: Patients with GA secondary to age-related macular degeneration (AMD), n = 246.

Intervention: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.

Main Outcome Measures: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.

Results: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.

Conclusions: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.
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http://dx.doi.org/10.1016/j.ophtha.2021.02.025DOI Listing
September 2021

Frequency of Urgent or Emergent Vitreoretinal Surgical Procedures in the United States During the COVID-19 Pandemic.

JAMA Ophthalmol 2021 04;139(4):456-463

Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York.

Importance: The American Academy of Ophthalmology (AAO) indicated that urgent or emergent vitreoretinal surgical procedures should continue during the coronavirus disease 2019 (COVID-19) pandemic. Although decreases in the frequency of critical procedures have been reported outside the field of ophthalmology, analyses are limited by volume, geography, and time.

Objective: To evaluate whether the frequency of ophthalmic surgical procedures deemed urgent or emergent by the AAO changed across the United States during the COVID-19 pandemic.

Design, Setting, And Participants: Vitreoretinal practices from 17 institutions throughout the US participated in this multicenter cross-sectional study. The frequency of 11 billed vitreoretinal Current Procedural Terminology (CPT) codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region (Northeast, Midwest, South, and West Coast), practice setting (academic [tax-exempt] or private [non-tax-exempt]), and date of respective statewide stay-at-home orders.

Main Outcomes And Measures: Nationwide changes in the frequency of billing for urgent or emergent vitreoretinal surgical procedures during the COVID-19 pandemic.

Results: A total of 526 536 CPT codes were ascertained: 483 313 injections, 19 257 lasers or cryotherapy, 14 949 RD repairs, and 9017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30 to May 2, 2020, with a maximal 38.6% decrease (from a mean [SD] of 437.8 [436.3] to 273.8 [269.0] injections) from April 6 to 12, 2020 (95% CI, -259 to -69 injections; P = .002). A weekly decrease was also identified that spanned a longer interval, at least until study conclusion (March 16 to May 31, 2020), for lasers and cryotherapy, with a maximal 79.6% decrease (from a mean [SD] of 6.6 [7.7] to 1.5 [2.0] procedures) from April 6 to 12, 2020 (95% CI, -6.8 to -3.3 procedures; P < .001), for RD repairs, with a maximal 59.4% decrease (from a mean [SD] of 3.5 [4.0] to 1.6 [2.2] repairs) from April 13 to 19, 2020 (95% CI, -2.7 to -1.4 repairs; P < .001), and for other vitrectomies, with a maximal 84.3% decrease (from a mean [SD] of 3.0 [3.1] to 0.4 [0.8] other vitrectomies) from April 6 to 12, 2020 (95% CI, -3.3 to -1.8 other vitrectomies; P < .001). No differences were identified by region, setting, or state-level stay-at-home order adjustment.

Conclusions And Relevance: Although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic's initial exponential growth phase. This decrease appears independent of region, setting, and state-level stay-at-home orders. It is unknown to what extent vitreoretinal intervention would have decreased without AAO recommendations, and how the decrease is associated with outcomes. Although safety is paramount during the COVID-19 pandemic, practices should consider prioritizing availability for managing high-acuity conditions until underlying reasons for the reduction are fully appreciated.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934075PMC
April 2021

Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes.

Am J Ophthalmol 2021 06 30;226:126-136. Epub 2021 Jan 30.

Retina Consultants of Texas, Houston, Texas, USA; Blanton Eye Institute (CCW), Houston Methodist Hospital, Houston, Texas, USA. Electronic address:

Purpose: To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME).

Design: Prospective, randomized phase 2 trial (PRIME).

Methods: A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI.

Results: Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence.

Conclusions: The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.
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http://dx.doi.org/10.1016/j.ajo.2021.01.024DOI Listing
June 2021

Risk of Blindness Among Patients With Diabetes and Newly Diagnosed Diabetic Retinopathy.

Diabetes Care 2021 03 20;44(3):748-756. Epub 2021 Jan 20.

Genentech, Inc., South San Francisco, CA.

Objective: To evaluate the association between initial diabetic retinopathy (DR) severity/risk of blindness in patients with newly diagnosed DR/good vision in the U.S.

Research Design And Methods: This retrospective cohort study evaluated adult patients with good vision (20/40 or better) and newly diagnosed DR between 1 January 2013 and 31 December 2017 (index date) in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS) Registry. The primary exposure of interest was DR severity at index: mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). The main outcome measure was development of sustained blindness (SB), defined as study eyes with Snellen visual acuity readings of 20/200 or worse at two separate visits ≥3 months apart that did not improve beyond 20/100.

Results: Among 53,535 eligible eyes (mean follow-up 662.5 days), 678 (1.3%) eyes developed SB. Eyes with PDR at index represented 10.5% (5,629 of 53,535) of the analysis population but made up 26.5% (180 of 678) of eyes that developed SB. Kaplan-Meier analysis revealed that eyes with moderate NPDR, severe NPDR, and PDR at index were 2.6, 3.6, and 4.0 times more likely, respectively, to develop SB after 2 years of DR diagnosis versus eyes with mild DR at index. In a Cox proportional hazards model adjusted for index characteristics/development of ocular conditions during follow-up, eyes with PDR had an increased risk of developing SB versus eyes with mild NPDR at index (hazard ratio 2.26 [95% CI 2.09-2.45]).

Conclusions: In this longitudinal ophthalmologic registry population involving eyes with good vision, more advanced DR at first diagnosis was a significant risk factor for developing SB.
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http://dx.doi.org/10.2337/dc20-0413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896265PMC
March 2021

Reply.

Ophthalmol Retina 2021 01;5(1):e1-e2

Retina Consultants of Houston, Houston, Texas; Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas.

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http://dx.doi.org/10.1016/j.oret.2020.09.022DOI Listing
January 2021

Effects of Long-Term DME Control With 0.2 µg/Day Fluocinolone Acetonide Implant on Quality of Life: An Exploratory Analysis From the FAME Trial.

Ophthalmic Surg Lasers Imaging Retina 2020 11;51(11):658-667

Background And Objective: Exploratory investigation of the effect of diabetic macular edema (DME) control with the 0.2 µg/day fluocinolone acetonide (FAc) intravitreal implant on quality of life (QOL) outcomes.

Patients And Methods: Post-hoc analysis of patients from the FAME study who received the FAc implant and had answered the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25) at baseline and Year 3 (N = 324). Patients were divided into quartiles (area under the curve [AUC]-central subfield thickness [CST]/day; n = 81/quartile). NEIVFQ-25 and best-corrected visual acuity (BCVA) changes were analyzed per quartile during a period of 3 years.

Results: NEI-VFQ-25 scores were significantly higher in patients with low AUC-CST/day (Quartiles 1 [P < .001] and 2 [P = .004]). Increases in NEIVFQ-25 subscale scores correlated with AUC-CST/day quartiles. BCVA significantly improved in patients with the lowest AUC-CST/day (Quartiles 1 and 2 [P < .001]).

Conclusion: There was a positive and sustained correlation between the long-term control of DME and patient-reported QOL outcomes for up to 3 years following a single FAc implant in patients with controlled DME. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:658-667.].
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http://dx.doi.org/10.3928/23258160-20201104-10DOI Listing
November 2020

Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration.

Ophthalmology 2021 07 19;128(7):1027-1038. Epub 2020 Nov 19.

Allergan, an AbbVie company, Irvine, California.

Purpose: To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD).

Design: Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data.

Participants: The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters.

Methods: At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630).

Main Outcome Measures: Efficacy measures included stable vision (<15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs).

Results: For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 μm, -146 μm, and -142 μm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively.

Conclusions: Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.
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http://dx.doi.org/10.1016/j.ophtha.2020.11.017DOI Listing
July 2021

Clinical Characterization of Suprachoroidal Injection Procedure Utilizing a Microinjector across Three Retinal Disorders.

Transl Vis Sci Technol 2020 10 22;9(11):27. Epub 2020 Oct 22.

Clearside Biomedical, Alpharetta, GA, USA.

Purpose: This study assessed physician-investigator experience with suprachoroidal (SC) injections, an investigational therapeutic administration technique using a 900 or 1100 µm microneedle to inject drugs into the SC space.

Methods: Datasets from six clinical trials across three diseases (noninfectious uveitis; diabetic macula edema, and retinal vein occlusion) were assessed. In addition to a user survey, retrospective correlations were performed between procedural variables (needle length), and demographics, and ocular characteristics.

Results: In the user survey, 84% (31/37) of physician-investigators did not perceive the SC injections to be meaningfully more challenging than other ocular injections. For the correlation analysis, the 900 µm needle was used for 71% (412/581) of baseline injections, and switching to the longer needle occured in the remaining 29% of baseline injections. No statistical correlations were found between needle lengths and age, race, disorder, refraction, visual acuity, intraocular pressure, retinal central subfield thickness, or lens status. Patient gender and needle length were statistically associated, with 76% (210/275) versus 66% (202/306) of injections administered with 900 µm needles for female and male gender, respectively. Injection quadrant correlated to needle length with 78% (214/275) of superotemporal quadrant injections administered with 900 µm needles, compared with 65% (73/113) of inferotemporal quadrant injections.

Conclusions: Both the user survey and the correlation analysis demonstrated that SC injection is well accepted by physician-investigators, and the two needle lengths accommodate a wide range of anatomic and demographic variables.

Translational Relevance: These results, along with the presented ex-vivo endoscopic imaging, suggest that SC injection could be readily adopted in clinical practice for targeted compartmentalized delivery of ocular therapeutics.
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http://dx.doi.org/10.1167/tvst.9.11.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585395PMC
October 2020

THE ANGIOPOIETIN/TIE PATHWAY IN RETINAL VASCULAR DISEASES: A Review.

Retina 2021 01;41(1):1-19

Genentech, Inc., South San Francisco, California; and.

Purpose: To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases.

Methods: A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites.

Results: The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed.

Conclusion: Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways.
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http://dx.doi.org/10.1097/IAE.0000000000003003DOI Listing
January 2021

Weakly-Supervised Vessel Detection in Ultra-Widefield Fundus Photography via Iterative Multi-Modal Registration and Learning.

IEEE Trans Med Imaging 2021 10 30;40(10):2748-2758. Epub 2021 Sep 30.

We propose a deep-learning based annotation-efficient framework for vessel detection in ultra-widefield (UWF) fundus photography (FP) that does not require de novo labeled UWF FP vessel maps. Our approach utilizes concurrently captured UWF fluorescein angiography (FA) images, for which effective deep learning approaches have recently become available, and iterates between a multi-modal registration step and a weakly-supervised learning step. In the registration step, the UWF FA vessel maps detected with a pre-trained deep neural network (DNN) are registered with the UWF FP via parametric chamfer alignment. The warped vessel maps can be used as the tentative training data but inevitably contain incorrect (noisy) labels due to the differences between FA and FP modalities and the errors in the registration. In the learning step, a robust learning method is proposed to train DNNs with noisy labels. The detected FP vessel maps are used for the registration in the following iteration. The registration and the vessel detection benefit from each other and are progressively improved. Once trained, the UWF FP vessel detection DNN from the proposed approach allows FP vessel detection without requiring concurrently captured UWF FA images. We validate the proposed framework on a new UWF FP dataset, PRIME-FP20, and on existing narrow-field FP datasets. Experimental evaluation, using both pixel-wise metrics and the CAL metrics designed to provide better agreement with human assessment, shows that the proposed approach provides accurate vessel detection, without requiring manually labeled UWF FP training data.
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http://dx.doi.org/10.1109/TMI.2020.3027665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513803PMC
October 2021

Automated vessel density detection in fluorescein angiography images correlates with vision in proliferative diabetic retinopathy.

PLoS One 2020 11;15(9):e0238958. Epub 2020 Sep 11.

Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America.

Purpose: To investigate the correlation between quantifiable vessel density, computed in an automated fashion, from ultra-widefield fluorescein angiography (UWFFA) images from patients with proliferative diabetic retinopathy (PDR) with visual acuity and macular thickness.

Methods: We performed a secondary analysis of a prospective randomized controlled trial. We designed and trained an algorithm to automate retinal vessel detection from input UWFFA images. We then used our algorithm to study the correlation between baseline vessel density and best corrected visual acuity (BCVA) and CRT for patients in the RECOVERY study. Reliability of the algorithm was tested using the intraclass correlation (ICC). 42 patients from the Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy (RECOVERY) trial who had both baseline UWFFA images and optical coherence tomography (OCT) data were included in our study. These patients had PDR without significant center-involving diabetic macular edema (central retinal thickness [CRT] ≤320μm).

Results: Our algorithm analyzed UWFFA images with a reliability measure (ICC) of 0.98. A positive correlation (r = 0.4071, p = 0.0075) was found between vessel density and BCVA. No correlation was found between vessel density and CRT.

Conclusions: Our algorithm is capable of reliably quantifying vessel density in an automated fashion from baseline UWFFA images. We found a positive correlation between computed vessel density and BCVA in PDR patients without center-involving macular edema, but not CRT.

Translational Relevance: Our work is the first to offer an algorithm capable of quantifying vessel density in an automated fashion from UWFFA images, allowing us to work toward studying the relationship between retinal vascular changes and important clinical endpoints, including visual acuity, in ischemic eye diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485882PMC
November 2020

Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study.

Am J Ophthalmol 2021 02 5;222:328-339. Epub 2020 Sep 5.

Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Purpose: To identify biomarkers for predicting response to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) and evaluate any links between cytokine expression and optical coherence tomography (OCT) phenotype.

Design: The IMAGINE is a post hoc image analysis and cytokine expression assessment of the Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE) randomized clinical trial.

Methods: Subjects were categorized as anatomical responders or nonresponders, and within the responder group as rebounders and non-rebounders based on quantitative, longitudinal OCT criteria. Retinal layer and fluid features were extracted using an OCT machine-learning augmented segmentation platform. Responders were further sub-classified by rapidity of response. Aqueous concentrations of 54 cytokines were measured at multiple timepoints. Expression was compared between responder groups and correlated with OCT imaging biomarkers.

Results: Of the 24 eyes studied, 79% were anatomical responders with 38% super responders, 17% early responders, and 25% slow responders. Twenty-one percent were nonresponders. Super responders had increased baseline vascular endothelial growth factor (VEGF) (880.0 pg/mL vs 245.4 pg/mL; P = .012) and decreased monocyte chemotactic protein-1 (MCP-1) (513.3 pg/mL vs 809.5 pg/mL; P = .0.042) concentrations compared with nonresponders. Interleukin-6 (-24.9 pg/mL vs 442.8 pg/mL; P = .032) concentrations increased among nonresponders during therapy. VEGF concentrations correlated with central subfield thickness (r = 0.49; P = .01). Panmacular retinal volume correlated with increased interleuckin-6 (r = 0.47; P = .02) and decreased MCP-1 (r = -0.45; P = .03). Matrix metallopeptidase-1 correlated with subretinal fluid volume (r = 0.50; P = .01).

Conclusions: OCT imaging biomarkers correlated with both intraocular cytokines and responsiveness to anti-VEGF therapy, which indicated a possible link to underlying pathways and their relevance to DME prognosis. Baseline concentrations of VEGF and MCP-1 are associated with anatomic response to anti-VEGF therapy.
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http://dx.doi.org/10.1016/j.ajo.2020.08.047DOI Listing
February 2021

Effect of Aflibercept on Diabetic Retinopathy Severity and Visual Function in the RECOVERY Study for Proliferative Diabetic Retinopathy.

Ophthalmol Retina 2021 05 1;5(5):409-419. Epub 2020 Sep 1.

Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, California; Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Purpose: To evaluate the effect of intravitreal aflibercept on diabetic retinopathy (DR) severity and visual function in patients with proliferative DR (PDR) without diabetic macular edema (DME).

Design: Prospective, longitudinal, multicenter clinical trial.

Participants: Forty eyes of 40 patients with PDR and no DME were enrolled in this study. Patients were randomized into monthly and quarterly 2-mg aflibercept injection cohorts and were treated over a period of 12 months.

Methods: All patients underwent ultra-widefield fundus imaging including pseudocolor and fluorescein angiography using an Optos 200Tx device.

Main Outcome Measures: Severity of DR at baseline, month 6, and month 12 was evaluated using the DR severity scale (DRSS). The DRSS scores were correlated with the 25-item Visual Function Questionnaire (VFQ-25) and 39-item Visual Function Questionnaire (VFQ-39) scores at baseline and month 12.

Results: Mean age of the patients was 48.2 years (range, 25-75 years), mean duration of diabetes mellitus was 16.1 years (range, 2-36 years), and median glycated hemoglobin level was 8.8% (IQR, 7.4%-10%). Both monthly and quarterly groups demonstrated a statistically significant regression in DRSS from baseline to month 12 (P < 0.001). The monthly group demonstrated a statistically significant greater regression of DRSS score at the month 6 visit compared with the quarterly group (P = 0.019). However, the difference between the two groups became statistically insignificant at month 12 visit (P = 0.309). Also no difference was found in mean VFQ-25 and VFQ-39 composite scores between the monthly and quarterly groups at month 12 (P = 0.947 and P = 0.921, respectively). The improvement in mean VFQ-25 and VFQ-39 composite scores at month 12 was correlated significantly with improvement in DRSS score (r = 0.384 and P = 0.039, and r = 0.361 and P = 0.046, respectively).

Conclusions: In this study of eyes with PDR without DME, both monthly and quarterly aflibercept injection groups showed significant improvement in DR severity at month 12 compared with baseline. The improvement in DRSS score was associated with an improvement in VFQ-25 and VFQ-39 composite score.
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http://dx.doi.org/10.1016/j.oret.2020.08.018DOI Listing
May 2021

Quantitative Comparison of Fundus Images by 2 Ultra-Widefield Fundus Cameras.

Ophthalmol Retina 2021 05 29;5(5):450-457. Epub 2020 Aug 29.

Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York; Center for Visual Sciences, University of Rochester, Rochester, New York; Mid Atlantic Retina, Retina Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

Purpose: To compare the relative number of retinal pixels and retinal area imaged using the Optos P200DTx (Optos PLC) and Zeiss Clarus 500 (Carl Zeiss Meditec AG) ultra-widefield (UWF) fundus cameras.

Design: Single-center retrospective cross-sectional analysis.

Participants: Seventy-eight eyes of 46 patients.

Methods: Eyes were imaged with Optos P200DTx, single-capture, and Zeiss Clarus 500, 2 capture montages when possible, UWF fundus cameras. Relative number of pixels encompassing all foveal-centered retinal quadrants were measured. Retinal area was measured with Zeiss Clarus 500 images that were registered to the Optos P200DTx images. Patients and technicians were asked for preferences between the machines. Imaging session times were recorded.

Main Outcome Measures: Relative number of retinal pixels and retina area captured by each fundus camera.

Results: Optos P200DTx consistently captured more relative pixels compared with Zeiss Clarus 500: 510.4 versus 355.6 (P < 0.001) in total with a similarly statistically significant trend in all 4 quadrants (P < 0.001 for each). For area calculation, 70 of the 78 images achieved successful registration. Optos captured a larger total retinal area: 765.6 versus 566.5 mm (P < 0.001) with a similarly statistically significant trend in all 4 quadrants. In the subset of 52 of 70 registered and montaged Zeiss Clarus 500 images, similar results were found. For peripheral pathologic features, Optos P200DTx captured unique findings in 28 images, and Zeiss Clarus 500 captured unique findings 1 image (P < 0.001). Among the 48 imaging sessions in which technicians preferred Optos P200DTx for 28 sessions (58%) and Zeiss Clarus 500 for 20 (42%; P = 0.15). Among patients who responded with a preference, 24 preferred Optos P200DTx and 20 preferred Zeiss Clarus 500 (P = 0.52). Average imaging session time was 4.6 minutes (standard deviation, 3.0 minutes) for Optos P200DTx and 5.2 minutes (standard deviation, 3.0 minutes) for Zeiss Clarus 500 (P = 0.17).

Conclusions: In the current study, the Optos P200DTx captured statistically significantly more retinal area in all 4 quadrants compared with the Zeiss Clarus 500. No statistically significant difference was found in patient or technician preference or image acquisition time between devices.
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http://dx.doi.org/10.1016/j.oret.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501635PMC
May 2021

Suprachoroidal CLS-TA plus Intravitreal Aflibercept for Diabetic Macular Edema: A Randomized, Double-Masked, Parallel-Design, Controlled Study.

Ophthalmol Retina 2021 01 20;5(1):60-70. Epub 2020 Aug 20.

Clearside Biomedical, Inc., Alpharetta, Georgia.

Purpose: This study evaluated the potential safety, efficacy, and durability advantages of investigational triamcinolone acetonide suspension (CLS-TA; Clearside Biomedical, Alpharetta, GA) administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of diabetic macular edema (DME).

Design: TYBEE was a prospective, controlled, double-masked study. Patients were randomized 1:1 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control), and assessed over 24 weeks.

Participants: Treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and central subfield retinal thickness (CST) of more than 300 μm.

Methods: Patients in the active group (n = 36) received CLS-TA and aflibercept at baseline and week 12. Patients in the control group (n = 35) received aflibercept at baseline, week 4, week 8, and week 12. To mask both groups, sham suprachoroidal and intravitreal injections were utilized. All patients were eligible to receive aflibercept as needed at weeks 4, 8, 16, and 20 per prespecified criteria.

Main Outcome Measure: Mean change in BCVA from baseline. Treatment differences were assessed with a 2-sided significance level of 0.10.

Results: Mean BCVA changes from baseline to week 24 were not statistically different in the active and control groups (intention-to-treat [ITT] population: +11.4 letters and +13.8 letters [P = 0.288]; per protocol [PP] population: +12.3 letters and +13.5 letters [P = 0.664]; respectively). Greater improvement in CST was seen in the active versus control group (ITT population: -212.1 μm and -178.6 μm [P = 0.089]; PP population: -226.5 μm and -176.1 μm [P = 0.035]; respectively). Compared with the control group, eyes in the active group received fewer treatments (scheduled plus as-needed treatments averaging 4.6 versus 2.6, respectively). No treatment-related serious adverse events were observed. Ocular adverse events were low for both arms. Cataract events, all assessed as unrelated to treatment, and events of elevated intraocular pressure trended higher in the active group.

Conclusions: CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden.
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http://dx.doi.org/10.1016/j.oret.2020.08.007DOI Listing
January 2021

Home Monitoring of Age-Related Macular Degeneration: Utility of the ForeseeHome Device for Detection of Neovascularization.

Ophthalmol Retina 2021 04 15;5(4):348-356. Epub 2020 Aug 15.

Retina Consultants of Houston, Houston, Texas; Blanton Eye Institute, Methodist Hospital, Houston, Texas. Electronic address:

Purpose: To evaluate the real-world utility of the ForeseeHome monitoring device (Notal Vision, Ltd., Tel Aviv, Israel) for the detection of conversion from intermediate age-related macular degeneration (iAMD) to neovascular AMD (nAMD) and to compare with results published by the Home Monitoring of the Eye (HOME) study.

Design: Retrospective analysis of electronic health records.

Participants: Eyes prescribed use of the ForeseeHome device across 4 retinal practices in the United States.

Methods: Usage information was collected from the online ForeseeHome portal for all eyes prescribed the device. For a predetermined subset of eyes, additional clinical information was collected through chart review and analyzed for clinical utility.

Main Outcome Measures: Frequency and length of use, number of eyes that used the device, number of eyes that established a baseline measurement, number of eyes that converted to nAMD, and number of alerts.

Results: Seven hundred seventy-five eyes of 448 patients were prescribed use of the ForeseeHome device. Six hundred forty-nine eyes (83.7%) used the device at least once; among this population, 478 (73.7%) established a baseline measurement. Patients who established a baseline measurement were significantly younger than those who did not (P < 0.001). Among eyes that established a baseline measurement, 126 (26.4%) had an overall inadequate frequency of use (≥2 tests per week), and 250 (52.3%) did not use the device as frequently as instructed by the manufacturer (≥3 tests per week); 24.7% of eyes discontinued use within 1 year. Of the 136 eyes that established a baseline measurement among 211 eyes prescribed the device at 1 clinical site, 52 alerts were recorded; 3 (6.8%) correctly identified conversion to nAMD and 47 (93.2%) represented false-positive alerts.

Conclusions: Compared with the prospective HOME study, the utility of the ForeseeHome device in the current analysis of clinical practice application was limited. A meaningful proportion of eyes never used the device or could not establish a baseline measurement. Overall frequency of use was low, and continuous use of the device decreased over time. A need exists for improvement in home monitoring technology for eyes with iAMD at risk of conversion to nAMD.
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http://dx.doi.org/10.1016/j.oret.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428765PMC
April 2021
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