Perspectives on the currently available pharmacotherapy for wet macular degeneration.

INTRODUCTION: Wet age-related macular degeneration (w-AMD) is a leading cause of visual impairment globally, with its prevalence expected to rise alongside increasing life expectancy. The current standard treatment involves frequent intravitreal injections of anti-VEGF agents, which although revolutionary, pose significant burdens on both patients and healthcare services. AREAS COVERED: This review explores current and emerging pharmaceutical treatments for w-AMD, focusing on their pharmacokinetics, pharmacodynamics, efficacy, and safety. Promising developments include extending treatment intervals with newer anti-VEGF agents like brolucizumab and faricimab, biosimilars offering cost-effective options, and exploring innovative drug delivery methods such as subretinal gene therapy. Combination therapies, gene therapies, and novel agents like KSI-301 and OPT-302 show potential for improving treatment outcomes and reducing treatment burden. EXPERT OPINION: While current treatments for w-AMD have significantly advanced with the advent of anti-VEGF therapies, their limitations in terms of treatment burden and incomplete responses have spurred research into diverse alternative approaches. These innovative strategies offer hope for improving patient outcomes and reducing healthcare burdens, suggesting a promising future for w-AMD management.

Ranibizumab Biosimilars in Treating Retinal Disorders: A Cost-Effective Revolution?

Ranibizumab, is a humanized, monoclonal antibody fragment that binds and inactivates vascular endothelial growth factor-A (VEGF-A) and VEGF-B. One of the main indications for an intravitreal treatment with ranibizumab is age-related macular degeneration (AMD), which is a retinal disease with a high worldwide socioeconomic impact. Biosimilars constitute biological products that demonstrate similar pharmacodynamic and pharmacokinetic characteristics with a reference product, as well as comparable clinical efficacy, safety and immunogenicity. Since the approval of the first biosimilar Razumab, there has been a variety of new biosimilars available on the market. They offer the advantage of the same good clinical and safety results at a better price. All Ranibizumab biosimilars that have gained approval were tested in double masked Phase 3 clinical studies. The use of Ranibizumab biosimilars in neovascular AMD is well reported in the bibliography. Nevertheless, over the last few years, there is a tendency of using biosimilars in other retinal diseases like retinopathy of prematurity (ROP), diabetic macular edema (DME) or polypoidal choroidal vasculopathy (PCV). In conclusion, ranibizumab biosimilars offer a promising avenue for the management of retinal diseases, especially in countries with lower socioeconomic status, where there is lack of availability of innovator ranibizumab. However, further research is required to fully explore their efficacy, safety, and long-term outcomes in a plethora of retinal diseases.

Barriers to care in neovascular age-related macular degeneration: Current understanding, developments, and future directions.

Neovascular age-related macular degeneration is the advanced and irreversible stage of age-related macular degeneration, the leading cause of severe vision loss in older adults. While anti-vascular endothelial growth factor injections have been shown to preserve or improve vision quality in eyes with neovascular age-related macular degeneration, the treatment regimen can be demanding of patients and caregivers, leading to lower rates of adherence. Therefore, it is crucial that disparities and obstacles in neovascular age-related macular degeneration care are identified to improve access to treatment. Review of the current literature revealed 7 major categories of barriers: travel burden, psychological barriers, financial burden and socioeconomic status, treatment regimen, other comorbidities, provider-level barriers, and system-level barriers. We provide an overview of the major barriers to neovascular age-related macular degeneration care that have been reported, as well as gaps in research that need to be investigated further.

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.

Associations with visual acuity outcomes after 12 months of treatment in 9401 eyes with neovascular AMD.

OBJECTIVE: To record visual acuity outcomes after 12 months of treatment for neovascular age-related macular degeneration (NvAMD), investigate variation between sites and explore associations with baseline characteristics and care processes. METHODS AND ANALYSIS: Anonymised demographic and clinical data were extracted from electronic medical records at treating National Health Service (NHS) Trusts. Associations with acuity outcomes were investigated using multivariate linear and logistic regression. RESULTS: Analysis included 9401 eyes (7686 patients) treated at 13 NHS Trusts. From baseline to month 12, median acuity improved from LogMAR 0.50 (IQR 0.30-0.80) to 0.40 (0.22-0.74) and the proportion of eyes with LogMAR ≥0.3 increased from 34.5% to 39.8%. Baseline visual acuity was the strongest predictor of visual acuity outcomes. For each LogMAR 0.1 worsening of baseline acuity, the acuity at 12 months was improved by LogMAR 0.074 (95% CI 0.073 to 0.074) and the odds of a 'poor' acuity outcome was multiplied by 1.66 (95% CI 1.61 to 1.70). Younger age, independent living status, lower socioeconomic deprivation, timely loading phase completion and higher number of injections were associated with better acuity outcomes. Despite case-mix adjustments, there was evidence of significant variation in acuity outcomes between sites. CONCLUSIONS: Even after adjustment for other variables, variation in acuity outcomes after NvAMD treatment within the NHS remains. Meaningful comparison of outcomes between different providers requires adjustment for a range of baseline characteristics, not visual acuity alone. Identifying best practice at sites with better outcomes and adapting local care processes are required to tackle this health inequality.

Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base.

Background: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch's membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran. Material and Methods: MarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling. Results: Risk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system. Conclusions: This study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.

The importance of monitoring wet age-related macular degeneration patients during Coronavirus disease 19 pandemic: A retrospective study of assessment of functional and structural outcomes.

OBJECTIVES: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the gold standard treatment for wet age-related macular degeneration (wet AMD). Coronavirus disease 2019 (COVID-19) has led to the cancellation of many scheduled intravitreal anti-VEGF injection visits. We compared the functional and structural visual outcomes of wet AMD patients who did not adhere to their planned intervals (group 1) with those who did (group 2). METHODS: Wet AMD patients of Swiss Visio Montchoisi and RétinElysée were included. Best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) changes between their first visit after the end of the first national lockdown in Switzerland (27 April 2020, first post-lockdown visit) and their last visit before the beginning of the first national lockdown in Switzerland (13 March 2020, last pre-lockdown visit) were assessed. The BCVA outcome was defined as unfavorable when there was a loss of≥5 ETDRS letters in the first post-lockdown visit compared to the BCVA at last pre-lockdown visit. The OCT outcome was defined as unfavorable when there was an increase in at least one of the parameters, intraretinal fluid (IRF), subretinal fluid (SRF), or pigment epithelial detachment (PED), at the first post-lockdown visit compared to the last pre-lockdown visit. MAIN RESULTS: Group 1 (89 patients, 109 eyes) had a 13.41% greater rate of unfavorable BCVA outcomes and a 38.27% greater rate of unfavorable OCT outcomes than group 2 (96 patients, 122 eyes) (P=0.04, P<0.0001, respectively). Multivariate analysis showed that the more the patients deviated from their programmed injections and the higher the BCVA pre-lockdown, the higher the rate of unfavorable BCVA outcomes (P=0.03 and P=0.02, respectively). OCT outcomes were not a predictive factor for an unfavorable BCVA outcome. CONCLUSIONS: The cancellation of many intravitreal anti-VEGF injection appointments resulted in worse functional and structural outcomes in wet AMD patients. The COVID-19 pandemic led many patients to refrain from their routine intravitreal anti-VEGF injection appointments, allowing us to analyze the role of designated intervals in the treatment of wet AMD. During any future lockdown due to COVID-19 or similar circumstances, continuity of care for wet AMD patients should be maintained.

Anti-Vascular Endothelial Growth Factor Treatment Discontinuation and Interval in Neovascular Age-Related Macular Degeneration in the United States.

PURPOSE: To assess the association between treatment interval and likelihood of anti-vascular endothelial growth factor (anti-VEGF) discontinuation among patients with neovascular age-related macular degeneration (nAMD) in a real-world setting in the United States. DESIGN: Retrospective clinical cohort study. METHODS: Health insurance claims data from the IBM MarketScan Commercial and Medicare Supplemental databases were retrospectively reviewed to identify adults with nAMD who received anti-VEGF for the first time between July 1, 2011, and June 30, 2017. The proportion of discontinued patients was analyzed using Kaplan-Meier curves. Cox proportional hazards models were used to examine the association between treatment intervals at 24 months and anti-VEGF discontinuation. RESULTS: The analysis included 8167 patients on continuous, unilateral anti-VEGF treatment for at least 24 months. Baseline demographics and clinical characteristics were well balanced between treatment interval groups. The overall rate of discontinuation from 24 months until 60 months after treatment initiation was 30.4%. At 60 months, patients on shorter treatment intervals were more likely to remain on treatment than those on longer intervals, ranging from 76.8% (4-week interval group) to 60.6% (>12-week interval group) and corresponding to a 28% lower likelihood (HR [SE] 0.72 [0.12], P < .01) and 55% higher likelihood of discontinuing treatment (HR [SE] 1.55 [0.07], P < .01), respectively, compared with the 8-week group. CONCLUSIONS: nAMD patients on longer anti-VEGF treatment intervals at 24 months had consistently higher discontinuation rates than patients on shorter intervals in the following years. This highlights the need to support and educate patients on long treatment intervals to continue with their treatment.

Cost of Ranibizumab Port Delivery System vs Intravitreal Injections for Patients With Neovascular Age-Related Macular Degeneration.

Importance: The study team investigated costs associated with the ranibizumab port delivery system (PDS) for neovascular age-related macular (nAMD), an alternative to conventional intravitreal anti-vascular endothelial growth factor (VEGF) injections. Objective: To investigate costs of intravitreal anti-VEGF injections vs ranibizumab PDS for patients with neovascular AMD (nAMD). Design, Setting, and Participants: This cost analysis used trial data and Medicare reimbursement rates and included patients with nAMD who were receiving ranibizumab, aflibercept, bevacizumab injections, or ranibizumab PDS. Main Outcomes and Measures: The number of intravitreal ranibizumab, aflibercept, and bevacizumab injections to break even with costs of ranibizumab PDS. Total direct medical costs over 1 year and 5 years for the ranibizumab PDS arm with refills at fixed 6-month intervals compared with monthly or bimonthly injections were calculated using Medicare rates. Scenario and sensitivity analyses accounted for uncertainty and variation. Results: The mean (SD) number of ranibizumab, aflibercept, and bevacizumab injections to break even with the cost of ranibizumab PDS with 1 refill was 10.8 (1.3), 9.3 (1.1), and 34.5 (4.2), respectively. Ranibizumab PDS with fixed 6-month refills over 1 year cost $21 016 ($2102). Comparatively, monthly intravitreal ranibizumab cost $1943 (95% CI, -$3047 to $6932; P = .34) more, aflibercept cost $5702 (95% CI, $253-$11 151; P = .04) more, and bevacizumab cost $16 732 (95% CI, -$20 170 to -$13 294, P < .001) less. For bimonthly injections, aflibercept cost $7658 (95% CI, -$11 649.52 to -$3665.61; P = .006) less. Over 5 years, monthly intravitreal ranibizumab projected to cost $25 581 (95% CI, $2275-$48 887; P = .04) more, aflibercept cost $44 374 (95% CI, $18 623-$70 125; P = .008) more, and bevacizumab cost $67 793 (95% CI, -$82 501 to -$53 085; P < .001) less than PDS with fixed refills (mean [SD] cost, $89 218 [$8921]). For bimonthly injections, aflibercept cost $22 422 (95% CI, -$40 287 to -$45,56; P = .03) less. In scenario analyses, ranibizumab PDS with refills as needed offered cost savings compared with real-world intravitreal ranibizumab or aflibercept use at 5 years but not at 1 year. Conclusions and Relevance: In this cost analysis, ranibizumab PDS with 1 refill cost more than intravitreal ranibizumab or aflibercept injections if less than or equal to approximately 11 or 10 injections, respectively, are required within the first year. Long term, if less than 4.4 and 3.8 injections are needed per refill, intravitreal ranibizumab and aflibercept is lower cost. Ranibizumab PDS costs more than intravitreal bevacizumab injections throughout scenarios.

DELAYED FOLLOW-UP IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED UNDER UNIVERSAL HEALTH COVERAGE: Risk Factors and Visual Outcomes.

BACKGROUND/PURPOSE: To report the rate of delayed follow-up visits (DFU), to identify risk factors of DFU, and to assess the impact of DFU on outcomes in neovascular age-related macular degeneration. METHODS: This retrospective study included all patients with neovascular age-related macular degeneration (n = 1,291) treated with antivascular endothelial growth factor injections between January 2013 and December 2020 in 2 centers in Quebec, Canada. A DFU was defined as a delay of ≥4 weeks than scheduled. Visual outcomes, especially ≥15 letters loss, were reported. RESULTS: A total of 351 patients (27.2%) experienced ≥1 DFU. Odds were greater among older patients ( P = 0.005), patients treated at the hospital rather than the clinic ( P < 0.001), and patients with worse initial visual acuity ( P = 0.024). A DFU was associated with a mean visual acuity loss of 4.2 ± 13.4 letters ( P < 0.001) and an increased incidence of intraretinal fluid and subretinal fluid ( P = 0.001, P = 0.005) at 6 months despite resumption of injections. Central foveal thickness increased after DFU but returned to pre-DFU visit at 6 months. CONCLUSION: The DFU rate in patients with neovascular age-related macular degeneration treated under a universal health care system was around 27%. Delayed follow-up visits caused significant decreases in visual acuity and increases in intraretinal fluid and subretinal fluid on optical coherence tomography that did not recover after injections resumption despite normalization of central foveal thickness.

Cost-effectiveness analysis of brolucizumab versus aflibercept for the treatment of neovascular age-related macular degeneration (nAMD) in Italy.

BACKGROUND: Age-related macular degeneration (AMD) is a common and chronic eye condition characterized by the presence of progressive degenerative abnormalities in the central retina (macula). Notably, neovascular, or wet, AMD (nAMD) occurs when new, abnormal blood vessels grow under the macula causing scarring of the macula itself and resulting in a loss of central vision, visual distortion, and an impaired capacity of perceiving colour contrast and intensity. Brolucizumab, a new generation anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody, was approved by the European Medicines Agency for the treatment of nAMD. The aim of this analysis is to evaluate the cost-effectiveness profile of brolucizumab, compared to the main therapeutic alternative available (aflibercept), for the treatment of nAMD. METHODS: The simulation of costs and outcomes was carried out using a Markov model over a time horizon of 15 years. In base-case, treatment effectiveness inputs for brolucizumab and aflibercept were extracted from the HAWK and HARRIER studies and from a network meta-analysis. The Italian National Healthcare Service (NHS) perspective was considered, therefore only healthcare direct costs (treatment acquisition, administration, adverse events, disease monitoring) were analysed. In the alternative scenarios, the societal perspective and a prolonged time horizon were considered. Model robustness was tested through sensitivity analyses. RESULTS: In the base-case analysis, brolucizumab was dominant over aflibercept (+ 0.11 years QALY gained and -€15,679 costs). Both one-way deterministic and probabilistic sensitivity analyses confirmed the robustness and reliability of base-case results. The results of the probabilistic sensitivity analysis showed that when the willingness to pay is equal to €50,000 per QALY gained, brolucizumab would be dominant in 84% of simulations and in the remaining simulations brolucizumab would be cost-effective compared to aflibercept. Results of the alternative scenarios and sensitivity analyses confirmed the results of base-case. CONCLUSION: The cost-utility analysis shows that brolucizumab is dominant over aflibercept. Treatment with brolucizumab reduces the economic impact of nAMD and determined a slight increase of quality-adjusted survival. This analysis gives a high level of confidence that the treatment with brolucizumab would reduce the burden of intravitreal injections, compared to aflibercept, a relevant therapeutic alternative in Italy.

Managed care opportunities and approaches to select treatment for sight preservation.

Anti-vascular endothelial growth factor therapies have become the mainstay of treatment for both diabetic macular edema and neovascular age-related macular degeneration. This treatment is imperative for vision preservation including visual acuity. However, treatment burdens include high costs, frequent injections, continued visual loss, and loss of ability to perform day-to-day functions. Although clinical trial data have provided insights to treatment options and protocols, real-world patient experiences and adherence to therapies do not often mimic clinical trials as patients cannot fully adhere to their treatment schedule, leading to poor disease outcomes. Payers may consider various strategies such as step therapies, fee schedule management, and driving utilization through specialty pharmacies to contain costs. However, it is important to recognize not all patients will respond to a one-size-fits-all approach to treatment, warranting a more personalized approach.

Retrospective Analysis of the Pharmaco-Utilization of VEGF Inhibitors and Health Care Costs among Patients with Wet Age-Related Macular Degeneration and Other Ocular Diseases in Italy.

This Italian retrospective study aimed to analyze the pharmaco-utilization of anti-VEGF drugs and health care costs among patients with wet age-related macular degeneration (wAMD) or other ocular diseases. A retrospective analysis was performed on administrative databases of Italian entities covering approximately six million individuals. Across January 2010-December 2017, patients aged ≥50 years with a prescription of intravitreal anti-VEGFs were included as "wAMD" patients [by wAMD hospitalization or intravitreal injections] or as "other ocular diseases" patients [by hospitalization for other ocular disorders or intravitreal injections, with concomitant diabetes diagnosis or dexamethasone treatment]. The date of first matching of inclusion criteria was index-date. wAMD-cohort. Overall, 3879 patients were included; at index-date, 82.2% were treated with Ranibizumab, 15.8% with Aflibercept, and 2% with Pegaptanib. During the follow-up, the mean/annual anti-VEGF prescription [3.6 (first-year)-0.8 (third-year)] and the total expenditure [5799.84 € (first-year)-3212.84 € (third-year)] decreased. Other ocular diseases-cohort. Overall, 2646 patients were enclosed; 85.9% were treated with Ranibizumab, 13.5% with Aflibercept, and 0.6% with Pegaptanib. During the follow-up, the mean/annual anti-VEGF prescription [3.3 (first-year)-0.5 (third-year)] and the total cost [7196.83 € (first-year)-5162.68 € (third-year)] decreased. This observational study highlighted a decline in anti-VEGF prescriptions over time in both cohorts, suggesting a trend of under-treatment that could worsen the patients' clinical outcomes and increase health care resource consumption.

Burden of disease assessment in patients with neovascular age-related macular degeneration in Spain: Results of the AMD-MANAGE study.

BACKGROUND/AIMS: The present study evaluates the burden of neovascular age-related macular degeneration (nAMD) to Healthcare System and patients, describing the management and treatment effectiveness in routine clinical practice in Spain. METHODS: Observational, non-interventional, cross-sectional, retrospective (24 months), multicentre study including patients who started treatment with licensed vascular endothelial growth factor inhibitors (anti-VEGF) for nAMD with a minimum follow up of 24 months. RESULTS: 126 evaluable patients were included with mean (SD) age of 79.1 (7.5) years. From diagnosis, it took a mean (SD) of 0.5 (0.5) months for the first treatment. Throughout 24 months, mean (SD) number of visits per patient was 16.0 (5.0), 9.4 (4.3) associated intravitreal injection. There were 1186 injection visits, 53.6% of them only with injection and 46.3% with injection and tests. After loading phase, preferred treatment regimens were T&E (46.0%), PRN (44.4%), fixed regimen (4.0%), and others (5.6%). Total number of visits in patients with T&E and PRN were 16.5 (5.7) and 15.5 (4.7), respectively. After complete loading phase, mean (SD) time between two consecutive treatment injections was 2.2 (1.6) months. 27.8% patients underwent a treatment change, being lack of response the most frequent reason to change (43.2%). Mean (SD) best-corrected visual acuity change was 2.1 (15.9) letters at 24 months. CONCLUSION: This study showed an important burden to Healthcare System and patients related to monitoring visits. More efficacious and longer lasting treatments could be useful to increase treatment intervals, thus reducing the burden of patients and caregivers and the use of healthcare resources.

Early detection of neovascular age-related macular degeneration: an economic evaluation based on data from the EDNA study.

BACKGROUND/AIMS: To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting. METHODS: A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon. RESULTS: SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS. CONCLUSIONS: Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.

Longitudinal assessment of type 3 macular neovascularization using 3D volume-rendering OCTA.

OBJECTIVE: To investigate the evolution of treatment-naive type 3 macular neovascularization (MNV) undergoing anti-vascular endothelial growth factor (VEGF) treatment through volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA). DESIGN: Retrospective observational study. PARTICIPANTS: Patients with type 3 MNV and age-related macular degeneration (AMD). METHODS: Included subjects had three loading injections of an anti-VEGF agent. The OCTA volume data at baseline and follow-up were processed with a previously published algorithm in order to obtain a volume-rendered representation of type 3 MNV. Progressive changes in type 3 lesions were analyzed via 3D OCTA volume rendering. RESULTS: A total of 14 treatment-naive eyes with type 3 MNV from 11 AMD patients (7 females) were included. At both baseline and follow-up visits, a type 3 MNV complex was identifiable. Each complex was composed of a mean number of 2.5 ± 0.7 vascular branches at baseline and 1.4 ± 0.6 at the follow-up visit (p < 0.0001). The mean changes in central macular thickness and visual acuity were significantly correlated with modifications in the number of type 3 MNV branches (ρ = -0.533, p = 0.049, and ρ = -0.581, and p = 0.040, respectively). CONCLUSIONS: This study demonstrated that type 3 lesions do not disappear completely after loading treatment, as indicated previously by histopathologic studies. Importantly, quantitative volume changes in type 3 lesions are directly associated with treatment response.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Brolucizumab can be cost saving and cost-effective compared with aflibercept and ranibizumab in the treatment of wet AMD. DISCLOSURES: 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.

Longitudinal Higher-Order OCT Assessment of Quantitative Fluid Dynamics and the Total Retinal Fluid Index in Neovascular AMD.

Purpose: The purpose of this study was to evaluate the feasibility of assessing quantitative longitudinal fluid dynamics and total retinal fluid indices (TRFIs) with higher-order optical coherence tomography (OCT) for neovascular age-related macular degeneration (nAMD). Methods: A post hoc image analysis study was performed using the phase II OSPREY clinical trial comparing brolucizumab and aflibercept in nAMD. Higher-order OCT analysis using a machine learning-enabled fluid feature extraction platform was used to segment intraretinal fluid (IRF) and subretinal fluid (SRF) volumetric components. TRFI, the proportion of fluid volume against total retinal volume, was calculated. Longitudinal fluid metrics were evaluated for the following groups: all subjects (i.e. treatment agnostic), brolucizumab, and aflibercept. Results: Mean IRF and SRF volumes were significantly reduced from baseline at each timepoint for all groups. Fluid feature extraction allowed high-resolution assessment of quantitative fluid burden. A greater proportion of brolucizumab participants achieved true zero and minimal fluid (total fluid volume between 0.0001 and 0.001mm3) versus aflibercept participants at week 40. True zero fluid during q12 brolucizumab dosing was achieved in 36.6% to 38.5%, similar to the 25.6% to 38.5% during the corresponding q8 aflibercept cycles. TRFI was significantly reduced from baseline in all groups. Conclusions: Higher-order OCT analysis demonstrates the feasibility of fluid feature extraction and longitudinal volumetric fluid burden and TRFI characterization in nAMD, supporting a unique opportunity for fluid burden assessment and the impact on outcomes. Translational Relevance: Detection and characterization of disease activity is vital for optimal treatment of nAMD. Longitudinal assessment of fluid dynamics and the TRFI provide important proof of concept for future automated tools in characterizing disease activity.

ASSESSMENT OF EARLY CHANGES IN SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER INITIATION OF TREATMENT WITH INTRAVITREAL AFLIBERCEPT (EYLEA) OVER A 12-WEEK PERIOD FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Multicenter French Study (START).

PURPOSE: To assess early changes in spectral-domain optical coherence tomography during the loading phase with intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration. METHODS: In this prospective, open-label, single-arm, multicenter study, patients with neovascular age-related macular degeneration, who were antivascular endothelial growth factor treatment-naïve, received three monthly initial doses of intravitreal aflibercept 2 mg. The primary outcome was the proportion of patients with dry spectral-domain optical coherence tomography at 12 weeks, defined as an absence of intraretinal edema, intraretinal cysts, subretinal fluid, and subretinal pigment epithelium fluid. RESULTS: Fifty eyes of 50 patients were investigated. At 12 weeks, 34.0% (17/50) had dry spectral-domain optical coherence tomography. Marked reductions were observed for all other spectral-domain optical coherence tomography parameters. The mean macular central thickness fell significantly from 463.2 ± 184.3 µm at baseline to 288.9 ± 76.8 µm at Week 12 (P < 0.0001). The mean best-corrected visual acuity also improved significantly from 61.0 ± 16.0 letters at baseline to 66.6 ± 19.0 letters at Week 12 (P = 0.0006). CONCLUSION: The anatomic and functional outcomes improved over the 12-week study period. All outcome variables peaked after the third aflibercept injection, confirming the benefit of three initial doses.