Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Imaging Features Associated with Progression to Geographic Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 5.

PURPOSE: To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural OCT. DESIGN: Consensus meeting. PARTICIPANTS: International group that included those with expertise in imaging and AMD basic science and histology, and those with Reading Center experience in AMD clinical trials. METHODS: As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA, risk of progression to GA, or both. Attendees undertook premeeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histologic features. Each of these different features were then discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees to refine the consensus definitions and descriptions further. RESULTS: Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypotransmission or hypertransmission), features frequently seen in eyes with atrophy (e.g., refractile drusen), and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). CONCLUSIONS: An international consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

Anti-Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration: Systematic Literature Review and Expert Opinion.

TOPIC: To summarize the rates of atrophy, risk factors, and atrophy-associated visual outcomes in patients with neovascular age-related macular degeneration (nAMD) who received anti-vascular endothelial growth factor (VEGF) treatment for macular neovascularization (MNV). CLINICAL RELEVANCE: Age-related macular degeneration is a leading cause of vision loss worldwide, and VEGF inhibitors are the primary treatment for nAMD. However, atrophy is observed frequently in eyes treated with anti-VEGF therapy, prompting questions regarding a causative role for these therapies in atrophy development. METHODS: PubMed was searched for articles published in the past 5 years (January 1, 2014, through January 10, 2019). Studies including atrophy outcome(s) in patients with age-related macular degeneration who received anti-VEGF treatment were included. Review articles, retrospective studies, case reports or studies, preclinical studies, prevalence data reports, and non-English studies were excluded. Randomization was not required. RESULTS: Overall, 145 studies were identified; 29 publications were included, with cohorts ranging from 8 to 1185 eyes. Imaging methods used to assess atrophy varied across studies. All studies confirmed the occurrence of atrophy, and when available, longitudinal data from the included studies demonstrated an increase in atrophy incidence over time. Key risk factors or phenotypes associated with atrophy were fellow eye atrophy, reticular pseudodrusen, increased injections, and type 3 lesion. In addition, visual acuity loss was noted with foveal atrophy. DISCUSSION: All studies demonstrated that atrophy occurs in the context of MNV treated with anti-VEGF therapy; however, it is not clear whether anti-VEGF treatment is causative of atrophy versus being associated with atrophy development. The included studies were not designed or powered to assess atrophy as a primary outcome. In addition, it is difficult to determine whether prognostic factors directly affect atrophy. Furthermore, patient populations in clinical trials do not necessarily represent real-world patients. Although phenotypes and risk factors may help to identify those at greater risk of atrophy developing, it is important to recognize that adequately treating exudative MNV remains the best option to optimize vision outcomes in patients with nAMD, particularly given the risk of vision loss with undertreatment observed in the real world.

Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group.

PURPOSE: To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data. DESIGN: Consensus meeting. PARTICIPANTS: An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists. METHODS: During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components. MAIN OUTCOME MEASURES: A consensus classification of neovascular AMD. RESULTS: The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated. CONCLUSIONS: The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4.

PURPOSE: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

PURPOSE: To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. METHODS: As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. MAIN OUTCOME MEASURES: A consensus classification system for atrophy and OCT-based criteria to identify atrophy. RESULTS: OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 µm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 µm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. CONCLUSIONS: A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings.

PURPOSE: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS: A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.

Extrafoveal choroidal neovascularization secondary to wet age-related macular degeneration treated with intravitreal bevacizumab.

Considering the risk of recurrence of extrafoveal or juxtafoveal lesions after thermal laser treatment and the risk of poor response to photodynamic therapy, it seems reasonable to discuss with the patient the risks and benefits of antiangiogenic therapy. A case of age-related macular degeneration with an extrafoveal choroidal neovascularization treated with a single injection of intravitreal bevacizumab is described. The patient showed both anatomic and visual acuity improvement at 1 month following treatment that persisted even at the 8-month follow-up visit. Further studies are needed to validate the real risk-benefit ratio of intravitreal bevacizumab for extrafoveal exudative lesions versus the current treatments available.

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial--VIP report no. 3.

PURPOSE: To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. DESIGN AND SETTING: Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. PARTICIPANTS: Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. METHODS: Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. MAIN OUTCOME MEASURES: The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. RESULTS: Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. CONCLUSIONS: Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials--TAP Report no. 5.

OBJECTIVE: To report vision and safety outcomes from an extension of a 2-year investigation evaluating verteporfin photodynamic therapy in patients with age-related macular degeneration with subfoveal choroidal neovascularization (CNV). DESIGN AND SETTING: Open-label extension of selected patients from 2 multicenter, double-masked, placebo-controlled, randomized clinical trials, the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation, at 22 ophthalmology practices in Europe and North America. PARTICIPANTS: Patients enrolled in the TAP Investigation and followed up for at least 24 months in whom verteporfin therapy to CNV might reduce the risk of further vision loss. METHODS: Before receiving verteporfin therapy in the extension, eligible patients signed a written informed consent form accompanied by an oral consent process approved by local institutional review boards. Methods were similar to those described for 1- and 2-year results, with follow-up examinations beyond 2 years continuing at 3-month intervals with a few exceptions, including that extension patients with fluorescein leakage from CNV were to receive open-label verteporfin therapy irrespective of their original treatment assignment. RESULTS: Of 402 patients in the verteporfin group, 351 (87.3%) completed the month 24 examination; 320 (91.2%) of these enrolled in the extension study. The enrolled participants included 124 (78.0%) of the 159 verteporfin-treated patients with lesions composed of predominantly classic CNV at baseline, of whom 105 (84.7%) completed the month 36 examination. Verteporfin-treated patients with this lesion composition at baseline who participated in the extension study, with or without a month 36 examination, appeared more likely to have a younger age, better level of visual acuity, absence of fluorescein leakage from classic CNV, or no progression of classic CNV beyond the baseline boundaries of the lesion at the month 24 examination compared with those who did not enroll in the extension. For the 105 patients with a predominantly classic baseline lesion composition who completed the month 36 examination, an average of 1.3 treatments were given from the month 24 examination up to, but not including, the month 36 examination. A letter score loss in the study eye of at least 15 from baseline for these patients occurred in 39 (37.5%) at the month 24 examination compared with 44 (41.9%) of these patients at the month 36 examination. Visual acuity changed little from the month 24 examination (mean, -1.9 lines) to the month 36 examination (mean, -2.0 lines) for these eyes. Verteporfin-treated patients had little change in the mean visual acuity lost and few or no additional instances of infusion-related back pain or photosensitivity reactions from month 24 to month 36. Two patients originally assigned to placebo had acute severe vision decrease within 7 days after verteporfin treatment during the extension. One patient originally assigned to verteporfin had acute severe vision decrease after verteporfin treatment of the fellow eye during the extension. CONCLUSIONS: Vision outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained relatively stable from month 24 to month 36, although only approximately one third of the verteporfin-treated patients originally enrolled with this lesion composition had a month 36 examination. From these results, the TAP Study Group identified no safety concerns to preclude repeating photodynamic therapy with verteporfin. Additional treatment was judged likely to reduce the risk of further vision loss. Caution appears warranted in the absence of comparison with an untreated group during the extension and since not all patients in the TAP Investigation participated in the TAP Extension.