Neovascular Age-related Macular Degeneration Research Articles

Factors Affecting Disease Stability After Intravitreal Brolucizumab Injection for Refractory Neovascular Age-Related Macular Degeneration.

The purpose of this study is to identify the factors affecting neovascular age-related macular degeneration (nAMD) disease stability after brolucizumab treatment. We retrospectively analyzed the medical records of 31 patients (31 eyes) with recalcitrant nAMD who were switched to brolucizumab after conventional anti-vascular endothelial growth factor (VEGF) treatment. We divided patients into two groups by treatment extension (TE) period: group 1 with TE < 12weeks (N = 16) and group 2 with TE ≥ 12weeks (N = 15). We compared outcomes between the groups at 2, 4, 8, and 12weeks, including morphological characteristics of choroidal neovascularization (CNV). Logistic regression analysis identified factors associated with TE ≥ 12weeks. Group 2 had a significantly greater proportion of patients with dry macula (subretinal and intraretinal fluids absent) than group 1 (60 vs. 12.5%) at 2weeks (P < 0.05). Best-corrected visual acuity (BCVA) and subfoveal choroidal thickness (SFCT) did not differ significantly between groups at all timepoints. Central subfield retinal thickness (CST) was significantly lower in group 2 at 2 (237.1 vs. 280.8μm; P < 0.05), 4 (224.0 vs. 262.9μm; P < 0.05), and 8weeks (216.8 vs. 331.1μm; P < 0.05). Group 2 had less vessel area (0.63 vs. 1.27 mm2; P < 0.05) and total vessel length (0.22 vs. 0.42mm; P < 0.05). Choriocapillaris flow deficit (CCFd) was significantly lower in group 2 (42.7 vs. 48.2%; P < 0.05). Dry macula at 2weeks (odds ratio [OR] = 8.3; P < 0.05) and a lower CCFd (OR = 0.73; P < 0.05) were associated with TE ≥ 12weeks. Early fluid-free status after switching to brolucizumab and choriocapillary function around CNV were prognostic factors for disease stability in nAMD refractory to anti-VEGF treatment.

Cost-effectiveness Analysis of Ranibizumab Biosimilar for Neovascular Age-Related Macular Degeneration and its Subtypes from the Societal and Patient Perspectives in Japan.

This study evaluated the cost-effectiveness of anti-vascular endothelial growth factor (VEGF) therapies for subtypes of neovascular age-related macular degeneration (nAMD) from the societal perspective, and for any nAMD from the patient perspective in Japan. A Markov model was developed to simulate the lifetime transitions of a cohort of patients with nAMD through various health states based on the involvement of nAMD, the treatment status, and decimal best-corrected visual acuity. Ranibizumab biosimilar was compared with aflibercept from the societal perspective regardless of treatment regimen for the analysis of three subtypes (typical nAMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP)). Two analyses from the patient perspective focusing on the treat-and-extend regimens were performed, one with a cap on patients' copayments and one without. Ranibizumab biosimilar was compared with branded ranibizumab, aflibercept, aflibercept as the loading dose switching to ranibizumab biosimilar during maintenance (aflibercept switching to ranibizumab biosimilar), and best supportive care (BSC), for patients with any nAMD. In the subtype analyses, ranibizumab biosimilar when compared with aflibercept resulted in incremental quality-adjusted life years (QALYs) of - 0.015, 0.026, and 0.009, and the incremental costs of Japanese yen (JPY) - 50,447, JPY - 997,243, and JPY - 1,286,570 for typical nAMD, PCV, and RAP, respectively. From the patient perspective, ranibizumab biosimilar had incremental QALYs of 0.015, 0.009, and 0.307, compared with aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. The incremental costs for ranibizumab biosimilar over a patient lifetime excluding the cap on copayment were estimated to be JPY - 138,948, JPY - 391,935, JPY - 209,099, and JPY - 6,377,345, compared with branded ranibizumab, aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. Ranibizumab biosimilar was demonstrated as a cost-saving option compared to aflibercept across all subtypes of nAMD, irrespective of the perspectives considered.

Faricimab in Neovascular AMD Complicated by Pigment Epithelium Detachment: An AI-Assisted Evaluation of Early Morphological Changes.

This study investigates the early temporal changes in pigment epithelial detachment (PED) morphology following treatment with faricimab in patients with neovascular age-related macular degeneration (nAMD). Utilizing an artificial intelligence (AI)-assisted approach, we provide a detailed quantification and characterization of the dynamics of these morphological changes. A prospective observational study was conducted on 22 eyes from 22 treatment-naïve patients with nAMD-associated PED (presenting either type 1 or type 3 macular neovascularization). Participants were administered intravitreal faricimab (6mg) at baseline and at days 30, 60, and 90. Comprehensive ophthalmic evaluations and spectral-domain optical coherence tomography (SD-OCT) imaging were conducted at baseline and at seven additional follow-up visits on days 1, 7, 14, 30, 60, 90, and 120. An AI-based automated segmentation algorithm was utilized to precisely quantify changes in PED volume, alongside intraretinal (IRF) and subretinal fluid (SRF) volumes, at each time point. Treatment with faricimab resulted in a significant reduction in mean PED volume, with an average decrease of 12% at day 1, 29% at day 7, 51% at day 14, 68% at day 30, 72% at day 60, 79% at day 90, and 84% at day 120 (p < 0.0001 for all time points). Similarly rapid and marked reductions were noted in both mean IRF (23.5% at day 1, 90.7% at day 14) and SRF (14.4% at day 1, 91.2% at day 14) volumes. The study also showed a statistically significant improvement in best-corrected visual acuity (BCVA) over the follow-up period, correlating with the reduction in PED volume. Faricimab demonstrates early and significant efficacy in improving PED architecture in patients with nAMD. The rapid morphological improvements observed in this study suggest faricimab may represent a valid therapeutic option for PEDs associated with nAMD.

PDK4-mediated metabolic reprogramming is a potential therapeutic target for neovascular age-related macular degeneration

Age-related macular degeneration (AMD) causes severe blindness in the elderly due to choroidal neovascularization (CNV), which results from the dysfunction of the retinal pigment epithelium (RPE). While normal RPE depends exclusively on mitochondrial oxidative phosphorylation for energy production, the inflammatory conditions associated with metabolic reprogramming of the RPE play a pivotal role in CNV. Although mitochondrial pyruvate dehydrogenase kinase (PDK) is a central node of energy metabolism, its role in the development of CNV in neovascular AMD has not been investigated. In the present study, we used a laser-induced CNV mouse model to evaluate the effects of Pdk4 gene ablation and treatment with pan-PDK or specific PDK4 inhibitors on fluorescein angiography and CNV lesion area. Among PDK isoforms, only PDK4 was upregulated in the RPE of laser-induced CNV mice, and Pdk4 gene ablation attenuated CNV. Next, we evaluated mitochondrial changes mediated by PDK1-4 inhibition using siRNA or PDK inhibitors in inflammatory cytokine mixture (ICM)-treated primary human RPE (hRPE) cells. PDK4 silencing only in ICM-treated hRPE cells restored mitochondrial respiration and reduced inflammatory cytokine secretion. Likewise, GM10395, a specific PDK4 inhibitor, restored oxidative phosphorylation and decreased ICM-induced upregulation of inflammatory cytokine secretion. In a laser-induced CNV mouse model, GM10395 significantly alleviated CNV. Taken together, we demonstrate that specific PDK4 inhibition could be a therapeutic strategy for neovascular AMD by preventing mitochondrial metabolic reprogramming in the RPE under inflammatory conditions.

Macular thickness and visual acuity are characterized by a quadratic nonlinear relation in previously treated neovascular AMD eyes.

To assess the associations between visual acuity (VA) and retinal thickness in age-related macular degeneration (AMD) eyes treated with anti-vascular endothelial growth factor (VEGF) therapy. Sixty-eight patients with neovascular AMD (68 eyes) undergoing anti-VEGF therapy with two years of follow-up imaging data after the initiation of treatment were retrospectively included. Linear and nonlinear regression analyses with curve fitting estimation were performed to explore the relationship between visual acuity and OCT-based parameters at the 3-month and 24-month follow-up visits. Regression analyses were also performed between visual acuity and the retinal thickness deviation which was calculated as the absolute value of the difference between measured and normative retinal thickness values. The VA was not associated with either foveal (R2 = 0.011 and p = .401 at 3 months; R2 = 0.032 and p = .142 at 24 months) or parafoveal (R2 = 0.045 and p = .081 at 3 months; R2 = 0.050 and p = .055 at 24 months) retinal thicknesses. Compared with the linear models, a quadratic function yielded a relative increase in the R2 coefficients. Conversely, the VA was linearly associated with foveal retinal thickness deviation (R2 = 0.041 and p = .037 at 24 months) and parafoveal retinal thickness deviation (R2 = 0.062 and p = .040 at 3 months; R2 = 0.088 and p = .014 at 24 months) values. Although there was no linear relationship between retinal thickness and VA, a weak but statistically significant linear relationship could be observed when a retinal thickness deviation was considered. This suggests that deviation-based parameters may be beneficial for structure-function correlations in the context of anti-VEGF therapy for neovascular AMD.

Efficacy and Safety of Efdamrofusp Alfa versus Aflibercept in Participants with Neovascular Age-Related Macular Degeneration: A Randomized, Double-Masked, Active-Controlled, Noninferiority, Phase 2 Trial

PurposeTo evaluate efficacy and safety of efdamrofusp alfa compared with aflibercept in neovascular age-related macular degeneration (nAMD). DesignRandomized, double-masked, multicenter, active-controlled, non-inferiority phase 2 study ParticipantsA total of 231 treatment-naïve and previously treated participants with active choroidal neovascularization secondary to nAMD were enrolled. MethodsEligible participants were randomized (1:1:1) to 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa or 2 mg aflibercept groups. Participants in all groups received three initial monthly loading doses, followed by treatment every 8 weeks with assessment every 4 weeks up to week 52. Main outcome measuresThe primary endpoint was the mean BCVA change from baseline to week 36. The pre-specified noninferiority margin was set as –5 letters (80% CI). ResultsEach treatment group included 77 participants. The mean BCVA changes from baseline to week 36 for 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa and aflibercept groups were +10.6, +11.4, +12.0 letters, respectively; Least Squares (LS) mean difference were –1.4 (80% CI: –3.5 to 0.7) between 2 mg efdamrofusp alfa and aflibercept, and –0.6 (80% CI: –2.7 to 1.6) between 4 mg efdamrofusp alfa and aflibercept. Mean central retinal thickness changes were consistent across groups. Adverse event rate was comparable among the groups. ConclusionsEfdamrofusp alfa demonstrated noninferiority to aflibercept in BCVA improvement, accompanied by a similar safety profile.

Interreader and Intermodality Variability in Macular Atrophy Quantification in Neovascular AMD: Comparison of 6 Imaging Modalities

Macular atrophy is a common complication in neovascular age-related macular degeneration (AMD) and is associated with poorer visual outcomes. This study evaluated inter-reader and inter-modality variability in measuring macular atrophy in previously-treated neovascular AMD eyes without exudation, using six imaging modalities. Prospective, cohort study. Thirty participants with previously-treated neovascular AMD, showing no signs of exudation at the time of enrollment, and exhibiting macular atrophy. During the same clinic visit, patients were imaged using six different imaging modalities: color fundus photography (CFP; Clarus, Carl Zeiss Meditec), near-infrared imaging (NIR; Spectralis; Heidelberg Engineering, Heidelberg, Germany), structural optical coherence tomography (OCT; Spectralis; Heidelberg Engineering, Heidelberg, Germany), green fundus autofluorescence (GAF; Clarus, Carl Zeiss Meditec), blue fundus autofluorescence (BAF; Spectralis; Heidelberg Engineering, Heidelberg, Germany), and pseudocolor imaging (MultiColor; Spectralis; Heidelberg Engineering, Heidelberg, Germany). Two readers independently measured the macular atrophy area. Inter-reader and inter-modality agreement. The 95% coefficient of repeatability (CR) was 5.98 mm2 for CFP, 4.46 mm2 for MultiColor, 3.90 mm2 for BAF, 3.92 mm2 for GAF, 4.86 mm2 for NIR, and 3.55 mm2 for OCT. Similarly, the coefficient of variation (CV) was lowest for the OCT-based grading at 0.08 and highest for the NIR-based grading at 0.28. Accordingly, the intraclass correlation coefficient (ICC) was 0.742 for CFP, 0.805 for MultiColor, 0.857 for BAF, 0.850 for GAF, 0.755 for NIR, and 0.917 for OCT. The 6 different imaging modalities presented measurements with different mean values, with only a limited number of comparisons not significantly different between the instruments, although measurements were correlated. The largest size of macular atrophy was with the structural OCT-based grading (median=4.65 mm2; interquartile range [IQR]=4.78 mm2) and the smallest was with the CFP-based grading (median=3.86 mm2; IQR=5.06 mm2). Inconsistencies arose from various factors. In patients with neovascular AMD, macular atrophy measurements vary significantly depending on the imaging technique used. CFP-based assessments yielded the smallest macular atrophy sizes, while structural OCT-based assessments produced the largest. These discrepancies stem from both the inherent limitations of each modality in assessing RPE atrophy and factors related to neovascularization, such as the coexistence of fibrosis.

Pre-Clinical Studies of a Novel Bispecific Fusion Protein Targeting C3b and VEGF in Neovascular and Nonexudative AMD Models.

KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

Interim Results of the Phase III Portal Extension Trial of the Port Delivery System with Ranibizumab in Neovascular Age-Related Macular Degeneration

ObjectiveThe Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration (nAMD). Portal (NCT03683251) is evaluating long-term safety and tolerability of the PDS in patients with nAMD who completed the phase II Ladder (NCT02510794) or phase III Archway (NCT03677934) trials. DesignMulticenter, nonrandomized, open-label, extension clinical trial. ParticipantsAll-PDS safety population (N = 555) comprises patients enrolled in Portal who completed Ladder or Archway. Due to data availability, efficacy population comprises Ladder-to-Portal patients only: patients who previously received PDS 10, 40, or 100 mg/ml pro re nata (as-needed [PRN]; n = 58, 62, 59, respectively) or monthly intravitreal ranibizumab 0.5-mg injections (monthly ranibizumab; n = 41) in Ladder and subsequently enrolled in Portal. MethodsLadder patients received PDS refill-exchanges PRN or monthly ranibizumab. Archway patients received PDS 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or monthly ranibizumab. Once enrolled in Portal, all patients receive PDS Q24W from day 1. Main Outcome MeasuresOcular adverse events of special interest (AESIs); changes from baseline in best-corrected visual acuity (BCVA) and center point thickness (CPT); supplemental ranibizumab treatment between refill-exchange procedures; PDS Patient Preference Questionnaire results. ResultsIn the All-PDS safety population (mean follow-up, 111 weeks), 137 (24.7%) patients had ≥ 1 ocular AESI; most common were cataract (11.4%), vitreous hemorrhage (6.1%), conjunctival thickening (bleb)/filtering bleb leak (6.3%). Endophthalmitis occurred in 11 of 555 (2.0%) patients. For Ladder-to-Portal patients previously treated with PDS 100 mg/ml or monthly ranibizumab, BCVA remained stable from baseline to month 48; mean (95% confidence interval) changes from baseline were 0.1 (−6.6, 6.8; n = 31) and 2.3 (−9.4, 14.1; n = 15) letters, respectively; CPT remained stable through month 48. Approximately 95% of patients did not need supplemental treatment before each refill-exchange for > 2 years since Portal enrollment. Of Ladder-to-Portal previous monthly ranibizumab patients, 92% preferred the PDS over injections. ConclusionsInterim results from Portal suggest 4-year maintenance of visual/anatomic outcomes with PDS 100 mg/ml, with the PDS preferred to monthly injections. Long-term safety profile of the PDS is well characterized.

Severe Intraocular Inflammation After Intravitreal Injection of Faricimab: A Single-Site Case Series of Six Patients

To describe the patient characteristics and clinical course of severe intraocular inflammation (IOI) following intravitreal injection (IVT) of faricimab. Retrospective case series. Case series at a single French academic center (Dijon University Hospital) where 263 patients were treated with faricimab IVT between January 9, 2024 and May 7, 2024. Over the 4-month period, a total of 1659 eyes (1338 patients) received anti-vascular endothelial growth factor (anti-VEGF) IVTs for a total of 3510 IVTs, of which 343 eyes (263 patients) received faricimab IVTs for a total of 971 IVTs. Overall, 6 pretreated eyes with neovascular age-related macular degeneration that were switched to faricimab developed severe unilateral IOI following faricimab IVT (1/162 injections [0.62%]), including 5 eyes presenting with a severe anterior and intermediate uveitis mimicking infectious endophthalmitis. All eyes were normotensive and presented with mild to moderate pain and predominantly moderate vitritis, associated with granulomatous keratic precipitates in 2 eyes and nonocclusive vasculitis in one eye. The clinical presentation, sterile vitreous sample culture, and rapid improvement with treatment made the diagnosis of infectious endophthalmitis unlikely. Four patients out of 6 did not recover their pre-IOI visual acuity, with an average visual loss of +0.2 logMAR. Two patients had positive antinuclear antibodies, including one with a history of cutaneous lupus. In this case series, we reported 6 cases of severe IOI after intravitreal faricimab over 4 months in a single French center with an estimated incidence rate of 0.6% per injection. Future real-world data will contribute to a better evaluation of the epidemiology of this rare inflammatory adverse event related to intravitreal faricimab.

Brolucizumab-associated intraocular inflammation in Indian patients by VRSI study group.

Concerns about brolucizumab's (Pagenax®) association with intraocular inflammation (IOI) limit its use despite its cost-effectiveness and efficacy. This multicentric study analyzes IOI incidence across 21 tertiary eyecare centers in India since its introduction in October 2020. To determine the real-world incidence rate of IOI in Indian patients secondary to intravitreal brolucizumab across 21 tertiary eye care centers in India. Retrospective multicentric, survey-based study. Data including number of patients treated, clinical indications, side effects encountered, and IOI case details was collected via Google Forms in 21 Indian tertiary eye care centers since October 2020. Mean, median, frequency, and standard deviation were calculated for statistical analysis. All centers used pro re nata protocol for brolucizumab injections with a minimum injection interval of 8 weeks. The incidence of IOI was 0.79% (21 events out of 2655 eyes). Treatment indications included idiopathic polypoidal choroidal vasculopathy, neovascular age-related macular degeneration, diabetic macular edema, and off-label uses. IOI was experienced after the first injection (57%) in majority of cases with a median onset of 14 days (range: 1-65 days). IOI was mild in 28.5%, moderate in 33%, and severe in 38% of cases. Eighteen out of 21 IOI eyes recovered preinjection best corrected visual acuity or better. Our study found a lower IOI incidence (0.79%) with brolucizumab (Pagenax) in Indian patients compared to previously reported literature. IOI events were mostly mild to moderate, and post-treatment, most patients improved or maintained BCVA. Larger prospective multicentric studies with PRN dosing protocol are needed to confirm these findings.

Nocturnal hypoxia and age-related macular degeneration.

Nocturnal hypoxia is common, under-diagnosed and is found in the same demographic at risk of age-related macular degeneration (AMD). The objective of this study was to determine any association between nocturnal hypoxia and AMD, its severity, and the high-risk sub-phenotype of reticular pseudodrusen (RPD). This cross-sectional study included participants aged ≥50 years with AMD, or normal controls, exclusive of those on treatment for obstructive sleep apnoea. All participants had at home, overnight (up to 3 nights) pulse oximetry recordings and multimodal imaging to classify AMD. Classification of Obstructive Sleep Apnea (OSA) was determined based on oxygen desaturation index [ODI] with mild having values of 5-15 and moderate-to-severe >15. A total of 225 participants were included with 76% having AMD, of which 42% had coexistent RPD. Of the AMD participants, 53% had early/intermediate AMD, 30% had geographic atrophy (GA) and 17% had neovascular AMD (nAMD). Overall, mild or moderate-to-severe OSAwas not associated with an increased odds of having AMD nor AMD with RPD (p ≥ 0.180). However, moderate-to-severe OSA was associated with increased odds of having nAMD (odds ratio = 6.35; 95% confidence interval = 1.18 to 34.28; p = 0.032), but not early/intermediate AMD or GA, compared to controls (p ≥ 0.130). Mild OSA was not associated with differences in odds of having AMD of any severity (p ≥ 0.277). There was an association between nocturnal hypoxia as measured by the ODI and nAMD. Hence, nocturnal hypoxia may be an under-appreciated important modifiable risk factor for nAMD.

Long-Term Impact of Diabetic Retinopathy on Response to Anti-VEGF Treatment in Neovascular AMD.

To explore the long-term effect of diabetic retinopathy on response to anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration-associated type 1 macular neovascularization (MNV) using optical coherence tomography angiography (OCTA). A total of 45 eyes with exudative neovascular age-related macular degeneration (nAMD) with type 1 MNV were included in the analysis. Among them, 24 eyes of 24 patients had no history of diabetes mellitus (DM) in their anamnesis and were assigned to the Not Diabetic group; 21 eyes of 21 patients had mild diabetic retinopathy and were included in the Diabetic group. We considered the following outcome measures: (1) best-corrected visual acuity changes; (2) central macular thickness; (3) MNV lesion area; and (4) MNV flow area. The OCTA acquisitions were performed at the following time points: (1) baseline visit, which corresponded to the day before the first injection; (2) post-loading phase (LP), which was scheduled at 1month after the last LP injection; and (3) 12-month follow-up visit. All morphofunctional parameters showed a significant improvement after the LP and at the 12-month follow-up visit. Specifically, both the Diabetic group and the Not Diabetic group displayed a significant reduction of MNV lesion areas at both the post-LP assessment (P = 0.026 and P = 0.016, respectively) and the 12-month follow-up (P = 0.039 and P = 0.025, respectively). Similarly, the MNV flow area was significantly decreased in both the Diabetic group and the Not Diabetic group at the post-LP assessment (P < 0.001 and P = 0.012, respectively) and at the 12-month follow-up (P = 0.01 and P = 0.035, respectively) compared to baseline. A smaller reduction in the MNV lesion area was observed in the Diabetic group at both the post-LP evaluation (P = 0.015) and the 12-month follow-up (P = 0.032). No other significant differences were found between the groups for the other parameters (P > 0.05). Our results indicated that the Diabetic group exhibited a smaller reduction in MNV lesion area after 12months of anti-VEGF treatment. This highlights the importance of considering diabetic retinopathy as a potential modifier of treatment outcomes in nAMD management, with DM serving as a crucial risk factor during anti-angiogenic treatment.

Analytical Characterization for Similarity Assessment Between an Aflibercept Biosimilar SB15 and Reference Product (Eylea®).

SB15 is a proposed biosimilar product of reference aflibercept (Eylea®), an approved biological drug product for retinal diseases including neovascular age-related macular degeneration (nAMD). This study aimed to assess the analytical similarity between SB15 and its commercially available reference product (RP) sourced from the United States (US-aflibercept) and European Union (EU-aflibercept) in terms of structural, physicochemical, and biological properties. A panel of state-of-the-art analytical methods was used for the comprehensive characterization of SB15 and US/EU-aflibercept. In terms of the structural and physicochemical properties, primary structure; post-translational modifications (PTM); higher-order structure; purity and impurities; charge variants; and glycosylation were compared. In addition, biological characterization including mechanism of action (MoA)-related and Fc-related biological activities was conducted. Analytical similarity between SB15 and US/EU-aflibercept was demonstrated. The primary and higher-order structure of SB15 was confirmed to be comparable to that of US/EU-aflibercept. In addition, there were no meaningful differences in the physicochemical properties in terms of size and charge heterogeneity between SB15 and its RP. SB15 and RP were similar in biological activities including MoA-related binding activities, potencies, and Fc-related biological functions. Consequently, SB15 was confirmed to be highly similar to US/EU-aflibercept. Based on a comprehensive analytical similarity assessment of structural, physicochemical, and biological properties, SB15 was demonstrated to be highly similar to US/EU-aflibercept RP, supporting safe and effective use of SB15.

Endophthalmitis in Eyes Treated with the Port Delivery System with Ranibizumab: Summary of Cases during Clinical Trial Development

The Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration. The United States Prescribing Information has a Boxed Warning for endophthalmitis and reports the incidence rate in patients developing endophthalmitis after receiving the PDS compared with monthly intravitreal ranibizumab. Endophthalmitis cases noted in the Boxed Warning, treatment outcomes, potential contributing factors, and potential mitigations are summarized. Retrospective review of endophthalmitis cases in PDS-treated patients in the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) and Portal (NCT03683251) trials. Endophthalmitis cases in the pooled all-PDS safety population (N= 555) including PDS patients in Ladder, Archway, or Portal. Ladder patients received PDS (10, 40, or 100 mg/ml) with pro re nata refill-exchanges. Archway patients received PDS 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W). Portal patients received PDS Q24W from day1. Clinical features, management, and visual outcomes were summarized. Cases were summarized by date of PDS implant and/or refill, other prior invasive procedures/refills, and preceding/concurrent conjunctival complications. Twelve endophthalmitis events were reported in 11 patients (11/555 [2.0%]) through March 12, 2021. All were cultured (3 were culture positive) and treated with intravitreal antibiotics. Two cases (2/555 [0.4%]) occurred in the immediate postoperative period (days 5 and 6). Nine cases occurred later (day range: 57-853), including 4 before the first refill-exchange (day range: 57-161). Five patients received between 1 and 11 refill-exchanges before the event (onset: 6-168 days after last refill-exchange). Seven cases (7/11 [63.6%]) had preceding/concurrent conjunctival complications. At last follow-up, 7 patients recovered vision to study baseline levels or ≥20/40; 4 patients experienced vision loss of ≥15 ETDRS letters. Endophthalmitis is a serious complication that can endanger vision after any ocular procedure, including PDS implantation. Most, but not all, of this limited series of endophthalmitis cases were late onset, associated with conjunctival breach, and recovered vision with treatment. Meticulous attention to PDS surgical techniques with vigilant monitoring of conjunctiva during follow-up may minimize risk of endophthalmitis. Prompt treatment is critical for optimizing patient outcomes. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Characterization and prevalence of ocular comorbidities and risk of legal blindness across the United States.

Vision loss is a top disability in the United States (US). Patients commonly present with multiple ocular diseases, but the extent to which this places them at risk for vision loss, and if sex and race impacts this, is poorly understood. This exploratory analysis evaluated which ocular comorbidities and demographics are at highest risk for visual impairment. A retrospective cross-sectional study was conducted through the TriNetX Analytics Network, an aggregated network encompassing over 90 million insured and uninsured patients across 50 healthcare organizations from all regions in the US. Patients with diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), glaucoma, and uveitis were included in this study. Ocular diseases and visual impairment were determined through ICD-10 codes. Prevalence and odds ratios were calculated while stratifying by sex and racial demographics. Statistical analyses were completed using RStudio and Excel with 95% confidence intervals calculated. The comorbid conditions with the highest prevalence of visual impairment were uveitis and RVO (39.94%), uveitis and neovascular AMD (37.61%), and uveitis and glaucoma (33.23%). The comorbidity with the highest odds for visual impairment was uveitis and RVO (POR 4.86; 95% CI 4.49, 5.26). Compared to white males, Black and Hispanic males were disproportionately affected by visual impairment across ocular comorbidities. This study quantified the prevalence and odds of visual impairment for unilateral and comorbid ocular disease, with the addition of uveitis causing the greatest increase. Black and Hispanic males were disproportionately affected by visual impairment across comorbid conditions.

Three-month outcomes of treatment with faricimab or aflibercept for neovascular age-related macular degeneration: a propensity score matching study in a Japanese population.

This study aimed to compare the treatment outcomes of patients with neovascular age-related macular degeneration (nAMD) who initially received faricimab or aflibercept treatment using propensity score matching (PSM) to align patient backgrounds. Patients with treatment-naïve nAMD who received either faricimab or aflibercept for three consecutive monthly injections as the loading phase were enrolled in this study. In the 1:1 PSM, sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and AMD subtypes in the pre-treatment state were selected as covariates. We examined the BCVA, CMT, CCT, and remaining fluid at 1-, 2-, and 3-month after the first injection. After PSM, 43 eyes were included in the faricimab and aflibercept group each. Both groups showed significant improvements in BCVA, CMT, and CCT at 1-, 2-, and 3-month after the initial injection compared with baseline. Meanwhile, no significant differences were observed between the two groups at any time point regarding BCVA, CMT, and CCT. At 1-month, 18.6% of patients in the faricimab group and 41.9% in the aflibercept group demonstrated residual subretinal fluid or intraretinal fluid, with a significant difference between the groups (P = 0.03). The BCVA improved after three loading injections of both faricimab and aflibercept. Faricimab may provide a favorable early treatment response in reducing subretinal fluid in a Japanese cohort.

Evaluation of OCT biomarker changes in treatment-naive neovascular AMD using a deep semantic segmentation algorithm.

To determine real-life quantitative changes in OCT biomarkers in a large set of treatment naive patients in a real-life setting undergoing anti-VEGF therapy. For this purpose, we devised a novel deep learning based semantic segmentation algorithm providing the first benchmark results for automatic segmentation of 11 OCT features including biomarkers for neovascular age-related macular degeneration (nAMD). Training of a Deep U-net based semantic segmentation ensemble algorithm for state-of-the-art semantic segmentation performance which was used to analyze OCT features prior to, after 3 and 12 months of anti-VEGF therapy. High F1 scores of almost 1.0 for neurosensory retina and subretinal fluid on a separate hold-out test set with unseen patients. The algorithm performed worse for subretinal hyperreflective material and fibrovascular PED, on par with drusenoid PED, and better in segmenting fibrosis. In the evaluation of treatment naive OCT scans, significant changes occurred for intraretinal fluid (mean: 0.03 µm3 to 0.01 µm3, p < 0.001), subretinal fluid (0.08 µm3 to 0.01 µm3, p < 0.001), subretinal hyperreflective material (0.02 µm3 to 0.01 µm3, p < 0.001), fibrovascular PED (0.12 µm3 to 0.09 µm3, p = 0.02) and central retinal thickness C0 (225.78 µm3 to 169.40 µm3). The amounts of intraretinal fluid, fibrovascular PED, and ERM were predictive of poor outcome. The segmentation algorithm allows efficient volumetric analysis of OCT scans. Anti-VEGF provokes most potent changes in the first 3 months while a gradual loss of RPE hints at a progressing decline of visual acuity. Additional research is required to understand how these accurate OCT predictions can be leveraged for a personalized therapy regimen.

Comparison between indocyanine green angiography and optical coherence tomography angiography for the detection of nonexudative macular neovascularization.

Patients with unilateral treatment-naïve exudative neovascular age-related macular degeneration (nAMD) were examined for the presence of nonexudative macular neovascularization (neMNV) in their fellow eye using a multimodal imaging approach. This is intended to determine the sensitivity of individual imaging methods, namely, indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA). In this retrospective cross-sectional study, ICGA images of the nonexudative eye were analyzed for the presence of plaques. SS-OCTA outer retinal segmentations were evaluated for neovascular flow in en-face scans and/or color-coded flow in B-scans. The findings were matched with a double-layer sign (DLS) or pigment epithelium detachment (PED) on conventional OCT. In total, neMNV was diagnosed in the fellow eye of 40 of 241 patients (17%) using a multimodal imaging approach employing both ICGA and SS-OCTA. 25 eyes (10%) showed neMNV in both modalities, while 7 (3%) were only detected by ICGA and 8 (3%) by OCTA alone. The sensitivities of ICGA therefore were 80% (32/40) and 83% (33/40) for OCTA. Of the 40 eyes with neMNV, OCT revealed DLS in 25/40 (63%) and PED in 17/40 (43%) of the cases. None of the modalities alone could detect all neMNV in the partner eye of Caucasians with unilateral treatment-naïve exudative nAMD. ICGA and OCTA showed comparable sensitivity. The combination of ICGA, OCTA, and OCT provides the most comprehensive screening for this AMD subtype.

In vivo monitoring of active subretinal fibrosis in mice using collagen hybridizing peptides

Subretinal fibrosis is associated with worse visual outcomes in patients with neovascular age-related macular degeneration. As there is a lack of optimal biomarkers and no method that directly detects collagen in the back of the eye, novel tools that monitor fibrosis-related changes in neovascular age-related macular degeneration are needed. Here, using two mouse models (the laser-induced choroidal neovascularization model, and the JR5558 mouse presenting with spontaneous subretinal neovascularization with fibrosis), we imaged active fibrotic lesions using fluorescently labeled collagen hybridizing peptides (CHPs), short peptides that bind to single α-chain collagen structures during collagen remodeling. JR5558 retinal pigment epithelium/choroid flat mounts showed CHP co-staining with fibrosis and epithelial mesenchymal transition-related markers; additionally, CHP histopathology staining correlated with in vivo CHP imaging. After laser-induced choroidal neovascularization, in vivo CHP binding correlated with laser intensity, histopathology CHP and fibronectin staining. Laser-induced choroidal neovascularization showed decreased CHP intensity over time in healing/regressing versus active scars in vivo, whereas increased CHP binding correlated with elevated fibrosis in JR5558 mouse eyes with age. In bispecific angiopoietin 2/vascular endothelial growth factor antibody-treated JR5558 mice, CHPs detected significantly decreased collagen remodeling versus immunoglobulin G control. These results demonstrate the first use of CHPs to directly image remodeling collagen in the eye and as a potential clinical optical biomarker of active subretinal fibrosis associated with ocular neovascularization.