Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review.

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars.

Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

PURPOSE: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. RESULTS: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. CONCLUSION: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.

Optical coherence tomography in the management of diabetic macular oedema.

Diabetic macular oedema (DMO) is the major cause of visual impairment in people with diabetes. Optical coherence tomography (OCT) is now the most widely used modality to assess presence and severity of DMO. DMO is currently broadly classified based on the involvement to the central 1 mm of the macula into non-centre or centre involved DMO (CI-DMO) and DMO can occur with or without visual acuity (VA) loss. This classification forms the basis of management strategies of DMO. Despite years of research on quantitative and qualitative DMO related features assessed by OCT, these do not fully inform physicians of the prognosis and severity of DMO relative to visual function. Having said that, recent research on novel OCT biomarkers development and re-defined classification of DMO show better correlation with visual function and treatment response. This review summarises the current evidence of the association of OCT biomarkers in DMO management and its potential clinical importance in predicting VA and anatomical treatment response. The review also discusses some future directions in this field, such as the use of artificial intelligence to quantify and monitor OCT biomarkers and retinal fluid and identify phenotypes of DMO, and the need for standardisation and classification of OCT biomarkers to use in future clinical trials and clinical practice settings as prognostic markers and secondary treatment outcome measures in the management of DMO.

PIGMENT EPITHELIAL DETACHMENT THICKNESS AND VARIABILITY AFFECTS VISUAL OUTCOMES IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e., height) and thickness variability on best-corrected visual acuity outcomes in patients with neovascular age-related macular degeneration in the Phase 3 HAWK and HARRIER trials. METHODS: Optical coherence tomography images from the pooled brolucizumab 6 mg and aflibercept 2 mg arms were analyzed for the maximum PED thickness across the macula at baseline through to week 96. Best-corrected visual acuity outcomes were compared in patients with different PED thickness and variability cut-off thresholds. RESULTS: Greater PED thickness at baseline or at week 12 was associated with lower mean best-corrected visual acuity gain from baseline to week 96 (baseline PED ≥200 µ m: +4.6 letters; <200 µ m: +7.0 letters; week 12 PED ≥100 µ m: +5.6 letters; <100 µ m: +6.6 letters). Eyes with the largest PED thickness variability from week 12 through week 96 gained fewer letters from baseline at week 96 (≥33 µ m: +3.3 letters; <9 µ m: +6.2 letters). Furthermore, increased PED thickness at week 48 was associated with higher prevalence of intraretinal and subretinal fluid. CONCLUSION: In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with neovascular age-related macular degeneration and greater neovascular activity.

OCT outcomes as biomarkers for disease status, visual function, and prognosis in diabetic macular edema.

OBJECTIVE: To evaluate disorganization of retinal inner layers (DRIL), as detected on spectral-domain optical coherence tomography (OCT) images, as a biomarker for diabetic macular edema (DME) activity, visual function, and prognosis in eyes with DME. DESIGN: Longitudinal prospective. METHODS: Post hoc correlation analyses were performed on data from a phase 2 clinical trial. Seventy-one eyes of 71 patients with treatment-naive DME received either suprachoroidally administered CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension) combined with intravitreal aflibercept or intravitreal aflibercept with a sham suprachoroidal injection procedure. DRIL area, maximum horizontal extent of DRIL, ellipsoid zone (EZ) integrity, and the presence and location of subretinal (SRF) and intraretinal fluid (IRF) were evaluated at baseline and week 24 by certified reading centre graders. RESULTS: At baseline, the area and maximum horizontal extent of DRIL were negatively correlated with best-corrected visual acuity (BCVA; r = -0.25, p = 0.05 and r = -0.32, p =0.01, respectively). Mean baseline BCVA progressively worsened with each ordinal drop in EZ integrity, improved with the presence of SRF, and was invariant to the presence of IRF. DRIL area and maximum extent were significantly decreased at week 24 (-3.0 mm2 [p < 0.001] and -775.8 mm [p < 0.001], respectively. At week 24, decreases in the area and maximum horizontal extent of DRIL were positively correlated with increases in BCVA (r = -0.40, p = 0.003 and r = -0.30, p = 0.04). Improvements in BCVA at week 24 were no different between patients showing improvement in EZ, SRF, or IRF and those showing no improvement or worsening from baseline. CONCLUSIONS: DRIL area and DRIL maximum horizontal extent were demonstrated to be novel biomarkers for macular edema status, visual function, and prognosis in eyes with treatment-naive DME.

Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial.

BACKGROUND/AIMS: To evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD). DESIGN: Prospective, double-masked, randomised, phase 3 trial. METHODS: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity. RESULTS: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups. CONCLUSIONS: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants.

Pushing Retinal Imaging Forward: Innovations and Their Clinical Meaning - The 2022 Ophthalmologica Lecture.

Retinal imaging has greatly expanded our understanding of various pathological conditions. This article presents a summary of the key points covered during the 2022 Ophthalmologica Lecture held at the Euretina Congress in Hamburg. The first part of the article focuses on the use of optical coherence tomography angiography to examine and comprehend the choroid in age-related macular degeneration (AMD). Subsequently, we delve into the discussion of the "postreceptor neuronal loss" theory in AMD, which was studied using en face structural optical coherence tomography (OCT). Following that, we explore pertinent findings obtained through cross-sectional OCT in retinal and optic nerve diseases, such as AMD, diabetic macular edema, pathologic myopia, central serous chorioretinopathy, and Leber's hereditary optic neuropathy.

Age-Related Alterations of the Macular Choroid in Healthy Eyes Assessed by Swept-Source Optical Coherence Tomography Angiography.

OBJECTIVE: To analyze age-related changes in the choroid in healthy eyes using swept-source optical coherence tomography angiography (SS-OCTA). PATIENTS AND METHODS: This was a cross-sectional, prospective, observational study enrolling 222 eyes of 116 healthy participants. SS-OCTA images were captured using the PLEX Elite 9000 (Carl Zeiss Meditec) with a 6 x 6 mm pattern centered on the fovea. Subfoveal choroidal thickness (CT) and choroidal volume (CV) were generated automatically through manufacturer tools available in the Advanced Retinal Imaging (ARI) hub network. Choroidal vascularity index (CVI) and choriocapillaris flow deficits (CCFD) were computed using ImageJ. RESULTS: CV was found to be significantly higher in women than men. Overall, there was a significant positive correlation between CVI and CCFD, and a significant negative correlation between CT and CV with age. The relationship, however, was more complex, as a decade-wise analysis showed that CT and CV increased until the second decade, followed by a decrease until the sixth decade, and then an increase again in the seventh and eighth decades. CVI was highest in the seventh decade. In contrast, CCFD increased consistently with age and in all the Early Treatment of Diabetic Retinopathy Study (ETDRS) rings. CONCLUSION: The choroidal blood flow and its thickness reduces as the age advances. While the choroidal flow deficits show a consistent increase with age and the distance from the foveal center, the relationship of other parameters with age is more complex. Having a normative database from healthy subjects is imperative for understanding the changes taking place in diseased states. Choroidal parameters can show significant variations with age. These differences are not uniform or consistent with age, highlighting the importance of a normative reference database to assess the significance of choroidal alterations associated with disease. [Ophthalmic Surg Lasers Imaging Retina 2023;54:526-534.].

Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration: A Phase 3 Randomized Clinical Trial.

Importance: Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy. Objective: To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD). Design, Setting, and Participants: This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up. Intervention: Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56. Main Outcomes and Measures: The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity. Results: The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 µm vs AFL, -115.7 µm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable. Conclusions and Relevance: In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD. Trial Registration: ClinicalTrials.gov Identifier: NCT04450329.

Fibrosis in neovascular age-related macular degeneration: A review of definitions based on clinical imaging.

Despite the success of antiangiogenic therapy in controlling exudation in neovascular age-related macular degeneration (nAMD), the involvement of the outer retina in fibrosis results in gradual vision loss over time. The development of drugs that prevent or ameliorate fibrosis in nAMD requires that it is accurately detected and quantified with reliable endpoints and identification of robust biomarkers. Achievement of such an aim is currently challenging due to the lack of a consensus definition of fibrosis in nAMD. As a first step towards the establishment of a clear definition of fibrosis, we provide an extensive overview of the imaging modalities and criteria used to characterize fibrosis in nAMD. We observed variety in the selection of individual and combinations of imaging modalities, and criteria for detection. We also observed heterogeneity in classification systems and severity scales for fibrosis. The most commonly used imaging modalities were color fundus photography, fluorescein angiography and optical coherence tomography (OCT). A multimodal approach was frequently utilized. Our review suggests that OCT offers a more detailed, objective and sensitive characterization than color fundus photography/fluorescein angiography. Thus, we recommend it as a primary modality for fibrosis evaluation. This review provides a basis for future discussions to reach a consensus definition using standardized terms based on a detailed characterization of fibrosis, its presence and evolution, and taking into consideration impact on visual function. Achieving this goal is of paramount importance for the development of antifibrotic therapies.

Microperimetry in Retinal Diseases.

Retinal microperimetry (MP) is a procedure that assesses the retinal sensitivity while the fundus is directly observed, and an eye tracker system is active to compensate for involuntary eye movements during testing. With this system, the sensitivity of a small locus can be accurately determined, and it has become an established ophthalmic test for retinal specialists. Macular diseases are characterized by chorioretinal changes; therefore, the condition of the retina and choroid requires careful and detailed evaluations to perform effective therapy. Age-related macular degeneration is a representative retinal disease in which the macular function has been evaluated by the visual acuity throughout the course of the disease process. However, the visual acuity represents the physiological function of only the central fovea, and the function of the surrounding macular area has not been sufficiently evaluated throughout the different stages of the macula disease process. The new technique of MP can compensate for such limitations by being able to test the same sites of the macular area repeatedly. This is especially useful in the recent management of age-related macular degeneration or diabetic macular edema during anti-vascular endothelial growth factor treatments because MP can assess the effectiveness of the treatment. MP examinations are also valuable in diagnosing Stargardt disease as they can detect visual impairments before any abnormalities are found in the retinal images. The visual function needs to be carefully assessed along with morphologic observations by optical coherence tomography. In addition, the assessment of retinal sensitivity is useful in the presurgical or postsurgical evaluations.

Effect of statins on the age of onset of age-related macular degeneration.

BACKGROUND: This study evaluated the relationship between statin use and the age of onset of age-related macular degeneration (AMD). METHODS: Electronic Health Records from 52,840 patients evaluated at University of California Los Angeles (UCLA) Ophthalmology Clinics and 9,977 patients evaluated at University of California San Francisco (UCSF) Ophthalmology Clinics were screened. Survival analysis was performed using Cox proportional hazards regression models and visualized using Kaplan Meier survival curves, with the following covariates-sex, ethnicity, smoking history, fluoxetine use, obesity, diabetes mellitus, and hypertension. RESULTS: 5,498 of 52,840 patients at UCLA were diagnosed with AMD. Statin use was associated with a later AMD onset (HR = 0.8823, p < 0.0001), while female sex (HR = 1.0852, p= 00,035), obesity (HR = 1.4555, p < 0.0001), and fluoxetine (HR = 1.3797, p= 0.0003) were associated with an earlier AMD onset. Non-hispanic black (HR = 0.5687, p < 0.0001) and hispanic ethnicities (HR = 0.8269, p= 0.0028) were associated with a later AMD onset. When stratifying for ethnicity, statins, fluoxetine, sex, and obesity were significant only within non-hispanic white subjects. Statin use was significant among patients with dry AMD (HR = 0.8410, p= 0.0001) but not wet AMD (0.9188, p= 0.0351). In the replication cohort, 526 of 9,977 patients at UCSF had AMD. Associations between statins (HR = 0.7643, p= 0.0033), non-hispanic black ethnicity (HR = 0.5043, p= 0.0035), and obesity (HR = 1.9602, p < 0.0001) on AMD onset were confirmed. CONCLUSIONS: In both cohorts, statin use and non-hispanic black ethnicity are associated with a later AMD onset, while obesity with an earlier AMD onset.

Endpoints for clinical trials in ophthalmology.

With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated.

Baseline retinal vascular bed area on ultra-wide field fluorescein angiography correlates with the anatomical outcome of diabetic macular oedema to ranibizumab therapy: two-year analysis of the DAVE Study.

PURPOSE: To determine the relationship between baseline retinal non-perfusion area (NPA) and retinal vascular bed area (RVBA) on ultra-wide field fluorescein angiography (UWF FA) and long-term response to intravitreal ranibizumab therapy in diabetic macular oedema (DMO). METHODS: A post-hoc, 2-year observational case series. Baseline UWF FA images (Optos 200Tx) of 40 eyes from 29 patients with diabetes mellitus and treatment naïve DMO in the DAVE (NCT01552408) study were montaged and stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The retinal vasculature was automatically extracted to calculate RVBA. NPA was manually delineated by two masked certified graders. RVBA and NPA were computed in mm2 automatically by adjusting for peripheral distortion and then correlated with the severity of DMO. RESULTS: While global NPA at baseline was not correlated to retinal thickness measurements, baseline NPA in the superior retina was associated with the macular volume (MV) improvement (P = 0.022). Multivariate analysis revealed a smaller RVBA at baseline was correlated with a better MV outcome at two-year follow-up after adjusting for confounding factors (P = 0.049). CONCLUSION: Eyes with smaller baseline RVBA appear to have a better long-term anatomic outcome of DMO.

Ophthalmic imaging in diabetic retinopathy: A review.

Retinal imaging has been a key tool in the diagnosis, evaluation, management and documentation of diabetic retinopathy (DR) and diabetic macular oedema (DMO) for many decades. Imaging technologies have rapidly evolved over the last few decades, yielding images with higher resolution and contrast with less time, effort and invasiveness. While many retinal imaging technologies provide detailed insight into retinal structure such as colour reflectance photography and optical coherence tomography (OCT), others such as fluorescein or OCT angiography and oximetry provide dynamic and functional information. Many other novel imaging technologies are in development and are poised to further enhance our evaluation of patients with DR.

Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography.

Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR). Methods: This prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR. Results: A total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preoperative HRMe could not be detected in all patients with proliferative DR who underwent internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005). Conclusions: UHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development. Translational Relevance: UHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.