A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Regulatable Complement Inhibition of the Alternative Pathway Mitigates Wet Age-Related Macular Degeneration Pathology in a Mouse Model.

Purpose: Risk for developing age-related macular degeneration (AMD) is linked to an overactive complement system. In the mouse model of laser-induced choroidal neovascularization (CNV), elevated levels of complement effector molecules, including complement C3, have been identified, and the alternative pathway (AP) is required for pathology. The main soluble AP regular is complement factor H (fH). We have previously shown that AP inhibition via subretinal AAV-mediated delivery of CR2-fH using a constitutive promoter is efficacious in reducing CNV. Here we ask whether the C3 promoter (pC3) effectively drives CR2-fH bioavailability for gene therapy. Methods: Truncated pC3 was used to generate plasmids pC3-mCherry/CR2-fH followed by production of corresponding AAV5 vectors. pC3 activation was determined in transiently transfected ARPE-19 cells stimulated with H2O2 or normal human serum (+/- antioxidant or humanized CR2-fH, respectively). CNV was analyzed in C57BL/6J mice treated subretinally with AAV5-pC3-mCherry/CR2-fH using imaging (optical coherence tomography [OCT] and fundus imaging), functional (electroretinography [ERG]), and molecular (protein expression) readouts. Results: Modulation of pC3 in vitro is complement and oxidative stress dependent, as shown by mCherry fluorescence. AAV5-pC3-CR2-fH were identified as safe and effective using OCT and ERG. CR2-fH expression significantly reduced CNV compared to mCherry and was correlated with reduced levels of C3dg/C3d in the retinal pigment epithelium/choroid fraction. Conclusions: We conclude that complement-dependent regulation of AP inhibition ameliorates AMD pathology as effectively as using a constitutive promoter. Translational Relevance: The goal of anticomplement therapy is to restore homeostatic levels of complement activation, which might be more easily achievable using a self-regulating system.

Efficacy of low-vision devices in elderly population with age-related macular degeneration.

Purpose: Age-related macular degeneration (AMD) is a common cause of blindness, residual damage to macular area in spite of treatment necessitates visual rehabilitation by means of low-vision aids (LVAs). Methods: Thirty patients suffering from different stages of AMD requiring LVAs were included in this prospective study. Patients with nonprogressive, adequately treated AMD were enrolled over a 12-month period, prescribed requisite LVAs and followed-up for a minimum 1-month period. Before and after provision of LVAs, near work efficiencies were evaluated by calculating reading speed as words per minute (wpm) under both photopic and mesopic light conditions, and impact of poor vision on activities of daily living (ADL) was quantified by modified standard questionnaire based on Nhung X et al. questionnaire. Results: Of the 30 patients mean studied with mean age of 68 ± 10 years, 20 patients (66.7%) had dry AMD in better eye and 10 (33.3%) had wet AMD. Post-LVA, near visual acuity improved significantly and all cases were able to read some letters on near vision chart with an average improvement of 2.4 ± 0.96 lines. The different LVAs prescribed were high plus reading spectacles (up to 10 D) in 23.3%, hand-held magnifiers in 53.3%, base in prisms in 10%, stand held magnifiers in 6.7%, and bar and dome magnifiers in 3.3%. Conclusion: LVAs are effective in visual rehabilitation in patients with AMD. Self-reported reduction in visual dependency and improvement in vision-related quality of life post use of aids corroborated perceived benefit.

Análisis de minimización de costos de brolucizumab para la DMAEh en Colombia / Cost minimization analysis of brolucizumab for wAMD in Colombia

Introducción: La degeneración macular asociada a la edad húmeda (DMAEh) tiene un impacto negativo en la calidad de vida. Brolucizumab es una alternativa efectiva y segura. Objetivo: Evaluar la diferencia en costos anuales de tratamiento entre brolucizumab 6 mg (esquema 6 LP → q12/q8), ranibizumab 0.5 mg (esquema Treat and Extend [TREX]) y aflibercept 2 mg (esquema TREX) para pacientes con DMAEh en Colombia. Materiales y métodos: Se realizó un análisis de minimización de costos con un horizonte temporal de cinco años y una tasa de descuento del 5%. Se consideraron costos médicos directos mediante fuentes locales. Se realizó un análisis de sensibilidad univariante. Resultados: El uso de brolucizumab implica un ahorro anual del 7.63% vs. aflibercept y del 12.8% vs. ranibizumab. Estos resultados fueron consistentes con los análisis de sensibilidad. Conclusiones: En un horizonte temporal de cinco años, brolucizumab es una tecnología costo-ahorradora para el tratamiento de la DMAEh en Colombia.

Background: Wet age-related macular degeneration (wAMD) has a negative impact on quality of life. Brolucizumab is an effective and safe alternative. Objective: To assess the difference in annual treatment costs between brolucizumab 6 mg (6 LP → q12/q8 schedule), ranibizumab 0.5 mg (Treat and Extend [TREX schedule]), and aflibercept 2 mg (TREX schedule), for patients with AMD in Colombia. Materials and methods: A cost minimization analysis was performed with a time horizon of five years and a discount rate of 5%. Direct medical costs were considered through local sources. A univariate sensitivity analysis was performed. Results: The use of brolucizumab implies an annual saving of 7.63% vs. aflibercept and 12.8% vs. ranibizumab. These results were consistent with the sensitivity analyses. Conclusions: In a time horizon of 5 years, brolucizumab is a cost-saving technology for the treatment of AMD in Colombia

Exploring challenges to nutrition intervention adherence using COM-B model among patients with wet age-related macular degeneration: a qualitative study.

OBJECTIVES: To explore challenges to nutrition intervention adherence using the Capability, Opportunity and Motivation-Behaviour (COM-B) model among wet age-related macular degeneration (AMD) patients. These factors should be considered in the development of potential support and intervention programmes to address these problems. DESIGN: A qualitative study was conducted with one-to-one and face-to-face interviews with wet AMD patients using a semi-structured question guide. Data were analysed based on COM-B model: capability (physical and psychological), opportunity (physical and social) and motivation (reflective and automatic). SETTING: Southwest Hospital of Chongqing Province in China. PARTICIPANTS: A convenient and purposive sample of 24 wet AMD patients were recruited. RESULTS: The themes and subthemes were identified: psychological capability: (1) insufficient knowledge of nutrition; (2) misconceptions about the disease and treatment; (3) knowledge conflict; physical capability: (1) physical restriction; (2) limited access to nutrition knowledge; physical opportunity: (1) communication between providers and patients; (2) health insurance and extra charges; (3) food environment; social opportunity: (1) stigma of disease; (2) family influence; reflective motivation: (1) self-efficacy; (2) attitude; (3) outcome expectancies; (4) lack of professional support; automatic motivation: (1) difficulties in changing eating habits; (2) mindset. CONCLUSION: Medical staff should pay much attention to the process of patients' nutrition intervention. In addition, it is also necessary to develop professional and internet-based intervention to modify the dietary behaviour and improve the management skills of the patients.

A Delphi study on the clinical management of age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) is one of the main causes of blindness and visual impairment worldwide. As achieving a dry macula is one of the main objectives in AMD management, the purpose of this work was to reach a consensus on the relevance of retinal fluid in function, disease activity control and treatment patterns. METHODS: Forty-seven Portuguese ophthalmologists specialized in AMD participated in a DELPHI panel. Two rounds of presential meetings were conducted and a cut-off of 80% or more of votes was defined to consider answers consensual. RESULTS: Consensus was reached for 11 out of 18 questions. These questions focused on the impact of anatomical results on visual acuity, standards exams and parameters to assess disease activity, frequency and factors which influence disease activity assessment, criteria to use non-fixed treatment regimens, usefulness of individualized regimens and conditions for treatment interruption. No consensus was obtained for relevance of the different fluid types in AMD prognosis, frequency of fluid presence assessment, factors commonly associated with progression to geographic atrophy, ideal conditions for a fixed treatment regimen, date of first disease activity assessment and parameters to monitor disease activity. CONCLUSIONS: Consensus was achieved for over half of the questions assessed through this Delphi study. The questions for which no consensus was reached concerned either subjects that need further investigation or monitoring times which are influenced by resource availability. Raising awareness for these issues will allow the improvement of AMD management and treatment.

The Anti-Inflammatory Effect of Hydrogen Gas Inhalation and Its Influence on Laser-Induced Choroidal Neovascularization in a Mouse Model of Neovascular Age-Related Macular Degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. Choroidal neovascularization (CNV) is the major pathologic feature of neovascular AMD. Oxidative damages and the ensuing chronic inflammation are representative of trigger events. Hydrogen gas (H2) has been demonstrated as an antioxidant and plays a role in the regulation of oxidative stress and inflammation. This experiment aimed to investigate the influence of H2 inhalation on a mouse model of CNV. METHODS: Laser was used to induce CNV formation. C57BL/6J mice were divided into five groups: the control group; the laser-only group; and the 2 h, 5 h, and 2.5 h/2.5 h groups that received laser and H2 inhalation (21% oxygen, 42% hydrogen, and 37% nitrogen mixture) for 2 h, 5 h, and 2.5 h twice every day, respectively. RESULTS: The severity of CNV leakage on fluorescence angiography showed a significant decrease in the H2 inhalation groups. The mRNA expression of hypoxia-inducible factor 1 alpha and its immediate downstream target vascular endothelial growth factor (VEGF) showed significant elevation after laser, and this elevation was suppressed in the H2 inhalation groups in an inhalation period length-related manner. The mRNA expression of cytokines, including tumor necrosis factor alpha and interlukin-6, also represented similar results. CONCLUSION: H2 inhalation could alleviate CNV leakage in a laser-induced mouse CNV model, and the potential mechanism might be related to the suppression of the inflammatory process and VEGF-driven CNV formation.

Hypertension affects the treatment of wet age-related macular degeneration.

PURPOSE: Due to population ageing as well as the high prevalence of hypertension and age-related macular degeneration (AMD) in elderly individuals, and the relationship between hypertension and AMD is unclear. Our research aimed to investigate the association between hypertension, wet AMD (wAMD) and the treatment strategy of wAMD patients affected by hypertension. METHODS: Data of wAMD patients at Zhongshan Ophthalmic Center, Sun Yat-sen University, between 1 January 2002 and 30 June 2019, were extracted from the electronic healthcare information system. wAMD patients were divided into subgroups by hypertension status, age, sex, the need for vitrectomy surgery and the number of anti-VEGF drug intravitreal injections that these were divided in 1-3 vs. >3 (available time from 1 January 2012 to 30 June 2019). RESULTS: A total of 3096 wAMD patients (41.7% female, 58.3% male) with an age range of 50-96 years (68.7 (SD 9.42) years) were included. wAMD was significantly associated with hypertension (p < 0.001). After adjustment for sex and age, Cox regression model showed a significant association between hypertension in wAMD patients and the number of injections (RR = 1.31, 95% CI: 1.13-1.50, p < 0.001). There was no significant association between hypertension and the need for vitrectomy (p = 0.82). CONCLUSIONS: wet AMD was associated with hypertension status, and after the regular series of three injections, wAMD patients with hypertension were more likely to receive anti-VEGF drug intravitreal injections than those without hypertension. These results may facilitate prospective research on the prevention of wAMD and contribute to the management of wAMD patients.

Silicone microbubbles after anti-vascular endothelial growth factor injections in patients with wet age-related macular degeneration: incidence, quantification and secondary optical coherence tomography artfacts.

PURPOSE: To report the incidence and quantity of silicone oil microbubbles and the relationship with the number of intravitreal anti-vascular endothelial growth factor (VEGF) injections and evaluate if microbubbles induce artefacts on optical coherence tomography (OCT) images. METHODS: Observational, descriptive, cross-sectional study. Patients with wet age-related macular degeneration were included who had been treated for 1 year minimally with anti-VEGF injections repackaged in the hospital pharmacy. Detection and quantification of silicone microbubbles by mydriatic biomicroscopic examination were conducted 1 month after the last injection. The numbers of microbubbles were quantified on a scale of 0-3: 0, none; 1 scarce (1-10 microbubbles); 2 moderate (10-30); or 3 numerous (>30). Shadowing on OCT images was classified as 0-3: 0, none; 1 obscuring some retinal layers; 2 obscuring all retinal layers; or 3 obscuring the retinal thickness. RESULTS: The study included 142 eyes of 98 patients (mean age, 82.4 years + 7.3; range, 65-97) treated with 2377 injections. Microbubbles were detected in 127 (89.4%) eyes, 62 (43.6%) with numerous microbubbles and 36 (25.4%) and 29 (20.4%), respectively, with scarce and moderate numbers. A positive correlation was found between the numbers of injections and intravitreal silicone (rho, 0.7). Optical coherence tomography (OCT) artefacts were detected in 11 eyes; the artefacts obscured all retinal layers in three eyes. No significant relationship could be established between the appearance of floaters and the microbubbles. CONCLUSION: The presence and number of silicone microbubbles were correlated with the number of intravitreal injections. Microbubbles can produce OCT artefacts, which can hinder the treatment decision.

Principal Cause of Poor Visual Acuity after Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 23.

PURPOSE: To analyze the principal cause for poor vision in eyes with best-corrected visual acuity (BCVA) of 20/200 or worse 2 years after neovascular age-related macular degeneration (nAMD). DESIGN: Prospective cohort study of participants enrolled in a clinical trial of oral supplements. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants whose eyes began anti-vascular endothelial growth factor (VEGF) therapy for incident nAMD and had data available at 2 years. METHODS: Participants underwent refracted BCVA testing, ophthalmoscopic examination, and fundus photography at baseline and annual visits. Self-reports of anti-VEGF injections were collected. MAIN OUTCOME MEASURES: Principal cause of BCVA of 20/200 or worse at 2 years, detected on fundus photography grading. RESULTS: Of the 594 eligible eyes, the number with BCVA of 20/200 or worse at 2 years was 56 (9.4%). Mean BCVA was 14.9 letters (standard deviation [SD], 12.3 letters; Snellen equivalent, 20/500), versus 70.1 letters (SD, 12.8 letters; Snellen equivalent, 20/40) in the other group. Of the 55 eyes with fundus photography available at 2 years, 33 (60.0%) had central macular atrophy and 22 (40.0%) had central subretinal fibrosis assessed as the principal cause for poor vision. The group with poor BCVA had a higher proportion of non-White participants (8.9% vs. 1.7%; P = 0.006), lower BCVA 2 years earlier (mean, 38.0 letters [SD, 26.7 letters; Snellen equivalent, 20/160] vs. 71.8 letters (SD, 11.9 letters; Snellen equivalent, 20/40]; P < 0.0001), higher proportion with macular atrophy 2 years earlier (26.8% vs. 12.3%; P = 0.003), higher proportion with macular hemorrhage (25.5% vs. 13.2%; P = 0.014), and fewer anti-VEGF injections (7.6 vs. 10.2; P = 0.001). CONCLUSIONS: Visual acuity data and fundus photography were obtained in a clinical trial environment, but were related to anti-VEGF therapy given in routine clinical practice. At 2 years after starting anti-VEGF therapy, almost 1 in 10 eyes showed BCVA at the level of legal blindness. From fundus photography grading, the cause of poor vision appeared to be macular atrophy in 60% and subretinal fibrosis in 40%. These data may be useful in understanding the long-term limits to good vision in nAMD.

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.

Treatment of age-related macular degeneration after cataract surgery: a study from the Swedish National Cataract and Macula Registers.

PURPOSE: To characterize pre- and perioperative factors associated with treatment for wet age-related macular degeneration (wet AMD) after cataract surgery. METHODS: This register-based cohort study with data from the Swedish National Cataract Register (NCR) and the Swedish Macula Register (SMR) from 2010 to 2017 compared eyes with and without preoperative AMD that had undergone cataract surgery and was subsequently treated for wet AMD to eyes not treated within the study period. All first-eye surgeries registered in the NCR from 2010 to 2017 and matching eyes found in the SMR that had undergone treatment for wet AMD ≥ 1 year after the cataract procedure were included. Data for cataract surgery date, age and gender, use of a blue-blocking IOL, preoperative visual acuity, ocular comorbidities, posterior capsule rupture and date of AMD treatment initiation were extracted. RESULTS: The only independent factor associated with postoperative treatment of wet AMD in both groups was female gender (67.3% vs. 58.8%, p < 0.001 and 66.4% vs. 60.6%, p = 0.001, respectively). Older age was an independent factor in eyes without preoperative AMD (78.4 ± 6.5 vs. 73.4 ± 9.6 years, p < 0.001). A blue-blocking IOL appeared to decrease the likelihood of subsequent wet AMD treatment slightly but not statistically significant in eyes with preoperative AMD (52.7% vs. 56.8%, p = 0.110). CONCLUSIONS: Some factors (female gender, high age) are associated with undergoing subsequent treatment for wet AMD to a higher extent. If the use of a blue-blocking IOL offers any protection from undergoing AMD treatment after cataract surgery, such an effect must be very small.

Value of Anti-Vascular Endothelial Growth Factor Gene Therapy for Neovascular Age-Related Macular Degeneration.

PURPOSE: To use discounted cash flow (DCF) analysis to estimate the value creation associated with anti-vascular endothelial growth factor (VEGF) genetic therapy for neovascular age-related macular degeneration (nAMD). DESIGN: Economic analysis. PARTICIPANTS: Adults undergoing serial intravitreal anti-VEGF injections in 1 eye for nAMD. METHODS: Discounted cash flow modeling with scenario analysis was used to derive a present value for a 1-time alternative treatment to lifelong anti-VEGF treatment for nAMD. Multiple sensitivity analyses were performed on the basis of patient age at time of first injection and frequency interval of intravitreal injection. MAIN OUTCOME MEASURES: Present values of DCF and scenario analyses. RESULTS: Discounted cash flow analysis of intravitreal anti-VEGF treatment for nAMD resulted in a base-case valuation of $208 420.61, $219 093.31, and $17 379.41 for a 1-time alternative treatment to aflibercept, ranibizumab, and bevacizumab, respectively. This figure covaried significantly with anti-VEGF agent according to the patient age at first injection ($78 323.19-$292 449.87) and frequency of injections ($148 422.91-$388 096.81). In addition, for bevacizumab, variability was driven by the hypothetical degree of clinical superiority of 1-time therapy to repeated intravitreal injections due to reduction in adverse events ($17 379.41-$18 250.79) or reduction in direct or indirect costs associated with age-related macular degeneration ($17 379.41-$657 406.55). CONCLUSIONS: Anti-VEGF gene therapy approaches can create significantly different value propositions based on the agent modeled, patient age at first injection, frequency of injections, and clinical profile of the medication. Although the use of aflibercept or ranibizumab as a comparative cost metric is logical from a bioequivalence perspective, the disparity in medication costs should not be the primary value driver in applied models. Instead, bevacizumab should be the base case ($17 379.41), with additional value driven from an improvement in quality of life through clinical superiority. A reduction in direct and indirect costs can be used to approximate the value from maintained visual acuity, which is elaborated in the DCF analysis approach described in this article. This model can serve as a basis for assessing the price ceiling of myriad gene therapy approaches. Given the high present values for these therapeutics, innovative costing and reimbursement mechanisms should be further explored, with contingencies for sustained efficacy.

The Timing of Large Submacular Hemorrhage Secondary to Age-Related Macular Degeneration Relative to Anti-VEGF Therapy.

PURPOSE: To characterize the timing of large submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) relative to anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: The study included 46 eyes of 46 patients with large SMH resulting from neovascular AMD selected to undergo pars plana vitrectomy with subretinal tissue plasminogen activator at the Mid Atlantic Retina group of the Wills Eye Hospital. METHODS: Patient charts were reviewed to identify baseline characteristics and anti-VEGF treatment details. OCT was used to evaluate pigmented epithelial detachments, SMH, and subretinal fluid before and after SMH. MAIN OUTCOME MEASURES: The timing of SMH in relation to last anti-VEGF injection, the anti-VEGF treatment status (i.e., naive, stable, or recently extended or shortened) at the time of SMH, and the length of the anti-VEGF treatment interval at the time of bleeding. RESULTS: Submacular hemorrhage occurred in 15 patients (36%) who were treatment naive. In patients treated with anti-VEGF, 19 (45%) had a stable treatment interval, 5 (12%) had a recently extended interval, and 3 (7%) had a shortened interval. The average treatment interval at the time of SMH was 6.8 weeks with a median of 7 total injections before SMH. Seven treated patients (26%) experience an SMH while having a 4-week dosing interval. The average time between last injection and SMH was 29 days. Forty-eight percent of patients treated with anti-VEGF agents experienced an SMH within 30 days of anti-VEGF injection. Chi-square analysis found SMH more likely to occur within 30 days of anti-VEGF injection than after 30 days. CONCLUSIONS: Large SMH in neovascular AMD in a treat-and-extend regimen does not seem to be associated with prolonged dosing intervals or recent interval extension, and a large proportion of such hemorrhages are likely to be a result of mechanisms other than loss of effective VEGF inhibition.