Impact of anti-VEGF treatment on development of proliferative diabetic retinopathy in routine clinical practice.

BACKGROUND: This study evaluated impact of anti-vascular endothelial growth factor (VEGF) treatment on proliferative diabetic retinopathy (PDR) development among patients with non-proliferative diabetic retinopathy (NPDR) in US real-world clinical practice. METHODS: This was a retrospective analysis of electronic medical records (Vestrum Health; January 2013 to June 2019) of eyes with baseline NPDR, without DME, and naïve to anti-VEGF treatment at index DR diagnosis. Eyes that received anti-VEGF and/or laser treatment over the course of study before development of PDR constituted the treated cohort while the remaining including those treated with laser constituted the anti-VEGF naïve cohort. Survival analysis via Kaplan-Meier method evaluated time to DME and PDR development by baseline NPDR severity, with anti-VEGF treatment as censoring variable. Baseline factors affecting PDR development were analyzed using Cox multivariable regression, censoring for anti-VEGF treatment. RESULTS: Among anti-VEGF-naive eyes, cumulative incidence of DME in eyes with mild (n = 70,050), moderate (n = 39,116), and severe NPDR (n = 10,692) at baseline was 27.1%, 51.2%, and 60.6%. Multivariable regression analysis identified baseline NPDR severity as the most significant predictor of PDR development over 48 months (hazard ratio [HR] [95% confidence interval {CI}] of 2.69 (2.65-2.72) for moderate vs mild NPDR and 6.51 (6.47-6.55) for severe vs mild NPDR). Cumulative incidence (95% CI) of PDR was 7.9% (7.4%-8.3%), 20.9%, (20.0%-21.7%) and 46.8% (44.4%-49.2%) over 48 months in eyes with mild, moderate, and severe NPDR at baseline, respectively. Among treated eyes with baseline severe NPDR, cumulative incidence of PDR at 48 months was 50.1% in eyes treated with laser (n = 546; HR [95% CI] vs no treatment: 0.8 [0.7-1.0]), 27.4% in eyes treated with anti-VEGF (n = 923; HR [95% CI]: 0.4 [0.4-0.5]), and 25.6% in eyes treated with anti-VEGF plus laser (n = 293; HR [95% CI]: 0.5 [0.4-0.7]) compared with 49.9% in eyes with no treatment (n = 8930). CONCLUSIONS: DME and PDR development rates increased with increasing baseline NPDR severity. Approximately half of anti-VEGF‒naive eyes with severe NPDR progressed to PDR within 4 years in US clinical practice. The progression rate from severe NPDR to PDR was approximately halved with anti-VEGF versus no treatment.

Loss to Follow up in Patients with Proliferative Diabetic Retinopathy Treated with Anti-VEGF Therapy and/or Panretinal Photocoagulation in the United States.

PURPOSE: To determine the rate of loss to follow up (LTFU) in patients with proliferative diabetic retinopathy (PDR) treated with anti-VEGF therapy and/or panretinal photocoagulation (PRP) in the United States. DESIGN: Retrospective cohort study using the national IRIS® (Intelligent Research in Sight) Registry data. SUBJECTS: A total of 73 595 eyes of 56 590 patients with PDR diagnosed between 2013 and 2015 and treated between 2013 and 2018. METHODS: Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Loss to follow up was no follow up within 12 months from last treatment. RESULTS: For patient eyes treated for PDR, 11.7% (95% CI, 11.5-12.0) were LTFU. Among patients with PDR treated with anti-VEGF therapy alone, PRP alone, and anti-VEGF and PRP, the rates of LTFU were 12.3% (95% CI, 11.8-12.7), 12.6% (95% CI, 12.1-13.0), and 10.8% (95% CI, 10.4-11.1), respectively. Risk factors for LTFU include Black or African American race/ethnicity (odds ratio [OR], 1.26; 95% CI, 1.13-1.41; P < 0.001), Hispanic ethnicity (OR, 1.28; 95% CI, 1.16-1.42; P < 0.001), Native American/Alaska Native or Native Hawaiian/Other Pacific Islander race/ethnicity (OR, 2.69; 95% CI, 2.14-3.38; P < 0.001), and unilateral disease (OR, 2.05; CI, 1.88-2.23; P < 0.001). Odds for LTFU were higher with patients with baseline vision of 20/50 to 20/200 (OR, 1.25; 95% CI, 1.15-1.36; P < 0.001) and with vision worse than 20/200 (OR, 1.22; 95% CI, 1.05-1.42; P = 0.01) than for patient eyes with a baseline visual acuity of 20/40 or better. Odds for LTFU were lower for Medicare Fee-for-Service (OR, 0.71; 95% CI, 0.64-0.79; P < 0.001) and Medicare Managed (OR, 0.66; 95% CI, 0.56-0.78; P < 0.001) compared with private insurance. Odds for LTFU were lower for patients treated in the Midwest (OR, 0.72; 95% CI, 0.64-0.81; P < 0.001) and West (OR, 0.83; 95% CI, 0.74-0.94; P = 0.003) compared with in the South region. CONCLUSIONS: The rate of LTFU is between 10% and 12% among patients with PDR who were treated with anti-VEGF injections and/or PRP. Risk factors include Black or African American race/ethnicity, Hispanic ethnicity, baseline vision worse than 20/40, private insurance, South region, and unilateral disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Safety and Efficacy of CLS-TA by Anatomic Location of Inflammation: Results from the Phase 3 PEACHTREE Clinical Trial.

PURPOSE: To explore the efficacy of CLS-TA, a proprietary suprachoroidal injectable suspension of triamcinolone acetonide, in noninfectious uveitis (NIU) with macular edema (ME), categorized by anatomic subtype. METHODS: Patients diagnosed with ME associated with NIU of any etiology and anatomic subtype were eligible for the phase 3 PEACHTREE trial of CLS-TA. Post-hoc analyses were performed, stratified by discrete anatomic subtype of uveitis (anterior, intermediate, posterior, and panuveitis.). RESULTS: Across all anatomic subtypes at 24 weeks, patients receiving CLS-TA at baseline and week 12 demonstrated mean increases in BCVA ranging from +12.1 to +15.9 letters, mean central subfield thickness (CST) improvement ranging from -120.1 µm to -189.0 µm, and IOP changes ranging from +0.5 to +3.1 mmHg. Overall, reports of adverse events were similar among subtypes. CONCLUSIONS: Irrespective of the uveitic anatomic subtype among patients treated for ME associated with NIU, a clinical benefit in participants treated with CLS-TA was demonstrated, with a comparable safety profile.

Shifts in ophthalmic care utilization during the COVID-19 pandemic in the US.

BACKGROUND: Healthcare restrictions during the COVID-19 pandemic, particularly in ophthalmology, led to a differential underutilization of care. An analytic approach is needed to characterize pandemic health services usage across many conditions. METHODS: A common analytical framework identified pandemic care utilization patterns across 261 ophthalmic diagnoses. Using a United States eye care registry, predictions of utilization expected without the pandemic were established for each diagnosis via models trained on pre-pandemic data. Pandemic effects on utilization were estimated by calculating deviations between observed and expected patient volumes from January 2020 to December 2021, with two sub-periods of focus: the hiatus (March-May 2020) and post-hiatus (June 2020-December 2021). Deviation patterns were analyzed using cluster analyses, data visualizations, and hypothesis testing. RESULTS: Records from 44.62 million patients and 2455 practices show lasting reductions in ophthalmic care utilization, including visits for leading causes of visual impairment (age-related macular degeneration, diabetic retinopathy, cataract, glaucoma). Mean deviations among all diagnoses are 67% below expectation during the hiatus peak, and 13% post-hiatus. Less severe conditions experience greater utilization reductions, with heterogeneities across diagnosis categories and pandemic phases. Intense post-hiatus reductions occur among non-vision-threatening conditions or asymptomatic precursors of vision-threatening diseases. Many conditions with above-average post-hiatus utilization pose a risk for irreversible morbidity, such as emergent pediatric, retinal, or uveitic diseases. CONCLUSIONS: We derive high-resolution insights on pandemic care utilization in the US from high-dimensional data using an analytical framework that can be applied to study healthcare disruptions in other settings and inform efforts to pinpoint unmet clinical needs.

The COVID-19 pandemic disrupted healthcare services globally, including eye care in the United States. Using a US eye disease database, we measured how the pandemic impacted patient visits for 261 eye diagnoses by comparing actual visit volumes for each diagnosis with what would have been expected without the pandemic. We identified groups of conditions with similar changes in visit levels and examined whether these shifts were related to characteristics of the diagnoses studied. We found extended decreases in patient presentations for most eye conditions, with greater reductions for less severe diagnoses, and with anomalies and differences in this trend across diagnosis categories and pandemic sub-periods. This highlights areas of potentially unmet need in vision care arising from the pandemic.

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results.

Purpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD). Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (<15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events. Results: Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% [3/123]), moderate (4.9% [6/123]), or severe (1.6% [2/123]) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥95.9% (≥118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 µm). Conclusion: Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.

Loss to Follow-up in Patients with Neovascular Age-Related Macular Degeneration Treated with Anti-VEGF Therapy in the United States in the IRIS® Registry.

PURPOSE: To determine the incidence of being lost to follow-up (LTFU) and nonpersistence in patients with neovascular age-related macular degeneration (AMD) treated with anti-VEGF injections in the United States. DESIGN: Retrospective cohort study using the IRIS® (Intelligent Research in Sight) Registry data. PARTICIPANTS: One hundred fifty-six thousand three hundred twenty-seven treatment-naive patients with neovascular AMD who subsequently were treated with anti-VEGF therapy from 2013 through 2015 and followed up through 2019. METHODS: Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Being LTFU was defined as no follow-up within 12 months from last intravitreal injection. Nonpersistence was defined as no follow-up within 6 months from last intravitreal injection. RESULTS: For neovascular AMD, 11.6% of patients (95% CI, 11.4%-11.7%) were LTFU, and 88.4% of patients were followed up within 12 months. The rate of being LTFU generally was higher with increasing age, with odds of being LTFU greatest for patients between 81 and 84 years of age (OR, 2.51; 95% CI, 2.31-2.74; P < 0.001) compared with patients 70 years of age and younger. Odds of being LTFU for Black or African American patients (OR, 1.32; 95% CI, 1.08-1.61; P = 0.007) were greater than for White patients. Odds of being LTFU were higher for patients with Medicaid insurance (OR, 1.27; 95% CI, 1.01-1.60; P = 0.04) and lower for patients with Medicare Fee-For-Service insurance (OR, 0.69; 95% CI, 0.64-0.74; P < 0.001) than for patients with private insurance. Furthermore, 14.3% (95% CI, 14.1-14.4) of patients were nonpersistent, and 85.7% of patients underwent follow-up within 6 months. Odds of nonpersistence also were greatest among patients between 81 and 84 years of age (OR, 2.13; 95% CI, 1.98-2.29; P < 0.001) compared with patients 70 years of age or younger. Odds of nonpersistence for Black or African-American patients (OR, 1.38; 95% CI, 1.15-1.65; P < 0.001) and Hispanic patients (OR, 1.13; 95% CI, 1.03-1.24; P = 0.009) were greater than odds for White patients. CONCLUSIONS: Nearly 1 of 9 patients with neovascular AMD treated with anti-VEGF injections became LTFU, whereas 1 of 7 patients were nonpersistent. Risk factors identified included increasing age, male sex, unilateral involvement, diabetes, Medicaid insurance, and race or ethnicity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Hemi- and Central Retinal Vein Occlusion Associated with COVID-19 Infection in Young Patients without Known Risk Factors.

PURPOSE: Venous thromboembolic complications have been reported in association with coronavirus disease 2019 (COVID-19) infection. We raised awareness regarding a potential temporal association between COVID-19 infection and retinal vein occlusion (RVO). DESIGN: Multicenter, retrospective, nonconsecutive case series. SUBJECTS: Patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection, were included. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. METHODS: This was a multicenter, retrospective, nonconsecutive case series including patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. MAIN OUTCOME MEASURES: Ophthalmic findings, including presenting and final visual acuity (VA), imaging findings, and clinical course. RESULTS: Twelve eyes of 12 patients with CRVO (9 of 12) or HRVO (3 of 12) after COVID-19 infection were included. The median age was 32 years (range, 18-50 years). Three patients were hospitalized, but none were intubated. The median time from COVID-19 diagnosis to ophthalmic symptoms was 6.9 weeks. The presenting VA ranged from 20/20 to counting fingers, with over half (7 of 12) having a VA of ≥20/40. OCT revealed macular edema in 42% of the eyes; of these, 80% (4 of 5) were treated with anti-VEGF injections. Ninety-two percent (11 of 12) had partial or complete resolution of ocular findings at final follow-up. Four eyes (33%) had retinal thinning, as determined using OCT, by the end of the study interval. The final VA ranged from 20/20 to 20/60, with 11 of the 12 (92%) eyes achieving a VA of ≥20/40 at a median final follow-up period of 13 weeks (range, 4-52 weeks). CONCLUSIONS: Although we acknowledge the high seroprevalence of COVID-19 and that a causal relationship cannot be established, we reported this series to raise awareness regarding the potential risk of retinal vascular events due to a heightened thromboinflammatory state associated with COVID-19 infection.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA).

PURPOSE: To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU). DESIGN: Open-label, prospective multicentre safety study. PARTICIPANTS: Thirty-eight subjects with NIU, with and without macular oedema (MO). METHODS: Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations. MAIN OUTCOME MEASURES: The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST). RESULTS: Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period. CONCLUSIONS: Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.

Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA).

PURPOSE: To assess the extended efficacy and safety of suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) among patients with macular oedema (ME) secondary to non-infectious uveitis (NIU). METHODS: Patients with uveitic ME were treated with suprachoroidal CLS-TA at baseline and week 12 of the Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial (PEACHTREE) study. Time to rescue was evaluated over 24 additional weeks for MAGNOLIA. Safety data, visual acuity and retinal central subfield thickness (CST) reduction were also evaluated. Of the 53 eligible patients (46 CLS-TA and 7 control), 33 patients were enrolled (28 CLS-TA and 5 control). RESULTS: Over the entire 48-week period for PEACHTREE and MAGNOLIA, the median time to rescue therapy was 257 days versus 55.5 days for the CLS-TA and sham-control arms, respectively. Of 28 CLS-TA treated patients who participated in MAGNOLIA, 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. Among CLS-TA patients not requiring rescue, there was a mean gain of 12.1 letters and mean CST reduction of 174.5 µm at week 48. No serious adverse events related to study treatment were observed. CONCLUSION: Approximately 50% of patients did not require additional treatment for up to 9 months following the last CLS-TA administration.

Discontinuation and loss to follow-up rates in clinical trials of intravitreal anti-vascular endothelial growth factor injections.

PURPOSE: Clinical trials are often designed to include homogenous, highly specific patient populations with many resources to reduce patient dropout. Results may not translate to real-world settings. We evaluated discontinuation and loss to follow-up (LTFU) rates in clinical trials of anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). METHODS: Retrospective meta-epidemiological study. The authors queried ClinicalTrials.gov for all completed trials of anti-VEGF injections for DME, AMD, or RVO. Of 658 trials identified, 582 were excluded for being non-interventional, <100 patients, terminating early, or missing study results. The remaining 76 trials of 27,823 patients were analyzed for discontinuation and LTFU rates. RESULTS: Mean discontinuation rate was 12.44% (SD 8.12%, range 0-54.12%), with higher rates among control (18.87%) than treatment arms (10.78%, p = .006). Mean LTFU rate was 1.84% (SD 1.78%, range 0-7.76%), with no differences by disease, treatment type, or treatment frequency. CONCLUSION: Discontinuation rates of major intravitreal anti-VEGF clinical trials were highly variable, suggesting even trials struggle with overall patient retention. Though trial LTFU rates were low, real-world outcomes may differ due to higher reported LTFU rates, which should be considered when extrapolating trial results to clinical practice.

Optical Coherence Tomography Anatomic and Temporal Biomarkers in Uveitic Macular Edema.

PURPOSE: To assess the relationship between best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) features in noninfectious uveitis (NIU)-related macular edema. DESIGN: Clinical cohort study from post hoc analysis of 2 phase 3 clinical trials. METHODS: Correlation and longitudinal treatment analyses were performed. Of 198 patients with NIU, 134 received suprachoroidal CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension), and 64 received sham, with 12.9% and 72%, respectively, receiving rescue therapy. RESULTS: At baseline, mean BCVA progressively worsened with each ordinal drop in central subfield ellipsoid zone (EZ) integrity. Eyes with normal baseline EZ experienced greater 24-week change in BCVA versus those with some degree of baseline EZ disruption (11.9 vs 9.4 letters, P = .006). In contrast, eyes with baseline central subfield cystoid spaces and/or subretinal fluid showed more improvement (13.7 or 17.2 letters, respectively) at 24 weeks, versus those without such findings (5.5 [P = .012] or 9.5 letters [P < .001], respectively). Longitudinal modeling for CLS-TA-treated eyes showed that central subfield thickness (CST) reached 90% of maximal improvement by week 3, whereas 90% maximal response in BCVA was not reached until week 9. CLS-TA-treated eyes that showed CST reduction of ≥50 µm at 4 weeks experienced a greater 24-week improvement in BCVA versus those without such an early response (14.6 vs 6.5 letters, P = .006 for difference). CONCLUSIONS: Pretreatment EZ integrity and the presence of central subfield cystoid spaces or subretinal fluid each predict improved therapeutic response to treatment in eyes with NIU. In CLS-TA treated eyes, longitudinal modeling shows CST improvement preceding BCVA improvement.

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

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.

Disease-modifying effects of ranibizumab for central retinal vein occlusion.

PURPOSE: To identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes. METHODS: A post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy. RESULTS: At 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: - 1.17 [sham], - 2.37 [ranibizumab 0.3 mg], - 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups. CONCLUSIONS: Ranibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.

Safety and Tolerability of Intravitreal Carotuximab (DE-122) in Patients With Persistent Exudative Age-Related Macular Degeneration: A Phase I Study.

Purpose: Carotuximab (DE-122) is a novel endoglin antibody that exhibits potent anti-angiogenic activity. The aim of this study was to evaluate the safety and tolerability of a single intravitreal injection of four ascending doses of carotuximab in patients with persistent exudative age-related macular degeneration (AMD). Methods: In an open-label, dose-escalating, sequential cohort study, patients with persistent exudative AMD were assigned to an intravitreal injection of carotuximab 0.5 mg, 1.0 mg, 2.0 mg, or 4.0 mg (n = 3 per group). Safety and change in central subfield thickness (CST), as measured by spectral domain-optical coherence tomography, were assessed from baseline until day 90. Rescue therapy with an anti-vascular endothelial growth factor medication was allowed on days 8, 30, and 60. Results: Seven patients (58%) experienced at least one adverse event (AE), including five patients (41.7%) who experienced one or more AEs in the study eye and two patients (16.7%) who experienced one or more non-ocular AEs. Posterior eye deposits were reported in one patient 2 days after receiving 1.0 mg, but they resolved spontaneously by day 43. A >50-µm reduction in CST on two consecutive visits was observed in four patients (33%), including one patient in each dose cohort. Conclusions: In this study, carotuximab was generally well tolerated, with no serious AEs reported, when administered as a single intravitreal injection to patients with persistent exudative AMD. Translational Relevance: Further characterization of the safety and efficacy of carotuximab will be needed to determine what role it may have in the treatment of exudative AMD.

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration.

PURPOSE: FHTR2163 is a novel antigen-binding fragment (Fab) directed against high-temperature requirement protein A1 (HtrA1). HTRA1 inhibition may preserve retinal integrity and slow disease progression in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This study examined the safety, pharmacokinetics, immunogenicity, and changes in the HTRA1-specific substrate Dickkop-related protein 3 (DKK3) in patients with GA who received FHTR2163. DESIGN: Phase I, open-label, single ascending dose escalation and multiple-dose expansion study. METHODS: Adults aged ≥ 50 years with GA secondary to AMD with best corrected visual acuity ranging between Snellen 20/125 and 20/400 were enrolled. In the first stage, a single intravitreal injection of FHTR2163 was given in 5 dose-escalation cohorts ranging from 1 to 20 mg (n = 3 patients/cohort; n = 15 total patients). The second stage evaluated the maximum tested dose of 20 mg administered every 4 weeks for 3 doses (n = 13 patients). RESULTS: No dose limiting toxicities or ocular serious AEs were reported. The most frequently reported AEs in the study eye were conjunctival hemorrhage (n = 7), conjunctival hyperemia (n = 4), and eye pain (n = 2). No non-ocular or ocular AEs were assessed as drug related. There were no clinically significant changes in ocular exams. A sustained pharmacodynamic effect of anti-HtrA1 was observed in the aqueous humor, as measured by levels of cleaved DKK3. CONCLUSIONS: FHTR2163, a novel Fab directed against HtrA1, was well tolerated with no DLTs or significant ocular AEs. The molecule when injected intravitreally for 3 doses showed a sustained pharmacodynamic effect at the maximum tested dose of 20 mg.

A Smart Mobile Application to Monitor Visual Function in Diabetic Retinopathy and Age-Related Macular Degeneration: The CLEAR Study.

PURPOSE: The purpose of this study was to determine if a mobile application, the Checkup Vision Assessment System, could reliably monitor visual acuity (VA) and metamorphopsia remotely versus standard VA reference tests in the clinic. With the current COVID-19 pandemic, an even greater need for remote monitoring exists. Mobile tools enhance the ability to monitor patients virtually by enabling remote monitoring of VA and Amsler grid findings. DESIGN: Prospective, multicenter reliability analysis. METHODS: Participants: Patients (N = 108) with near corrected VA better than 20/200 and a diagnosis of age-related macular degeneration, diabetic retinopathy, or healthy patients without retinal disease (best-corrected visual acuity [BCVA] of 20/32 or better). INTERVENTION: participants were tested using the Checkup, reference VA, and Amsler tests, with the order of testing (Checkup or reference) randomized. Patients monitored their vision using Checkup at least twice a week at home between office visits. Main outcome measurements were near corrected VA and Amsler grid test results. RESULTS: Agreement was strong between Checkup and reference tests for VA (r = 0.86) and Amsler grid (sensitivity: 93%; specificity: 92%). Home versus clinic testing showed excellent agreement (r = 0.96). Patients reported successful home use. There were no serious adverse events or discontinuations. Patients rated the usability of Checkup to be excellent. CONCLUSIONS: There was good agreement between Checkup and in-clinic test results for VA and Amsler grid. The low variance of Checkup testing, agreement between in-clinic and home results, and excellent usability support Checkup as a reliable method for monitoring retinal pathology in clinic and home settings.