Endothelial Growth Factor Therapy Research Articles

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

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. 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. 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. 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. CRD42022314418.

Wide-field swept-source OCT angiography of the periarterial capillary-free zone before and after anti-VEGF therapy for branch retinal vein occlusion

BackgroundThe aim of the study was to investigate the changes in the periarterial capillary-free zone (paCFZ) after anti-vascular endothelial growth factor (VEGF) therapy in patients with branch retinal vein occlusion (BRVO) by wide-field swept-source optical coherence tomography angiography (SS-OCTA) and assess their associations with clinical outcomes.MethodsIn this retrospective observational study of 54 treatment-naïve BRVO patients with macular edema, we reviewed the findings of 12 × 12 mm2 SS-OCTA at baseline, 3, 6, and 12 months after intravitreal ranibizumab injections. The paCFZ and major retinal artery areas were measured on SS-OCTA images. The paCFZ area to artery area (P/A) ratio was calculated.ResultsThe paCFZ areas and P/A ratios of first- and second-order arteries were significantly greater in BRVO eyes than in contralateral eyes (all P < 0.01), but there were no differences in the first- and second-order artery areas (P = 0.20 and 0.25, respectively). The paCFZ areas and P/A ratios decreased significantly at 3, 6, and 12 months after anti-VEGF therapy (all P < 0.01). The baseline P/A ratio was significantly correlated with the baseline best-corrected visual acuity (BCVA), central retinal thickness, and their improvements at 3, 6, and 12 months (all P < 0.05). Baseline BCVA and P/A ratios of first- and second-order arteries were independently associated with the final BCVA in multivariate linear regression.ConclusionsWide-field SS-OCTA shows that anti-VEGF therapy can lead to a significant improvement in the paCFZ parameters in BRVO. Smaller baseline P/A ratios on SS-OCTA tend to predict better visual outcomes at 12 months after anti-VEGF therapy.

46-OR: Differential Effects of RBP3 and Anti-VEGF on Retinal Dysfunctions in Diabetic Retinopathy

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of severe diabetic retinopathy (DR) , but significant subset of patients showed inadequate response to anti-VEGF. We have previously reported that retinol binding protein 3 (RBP3) prevented hyperglycemia induced retinal pathologies and progression to severe DR. Hypothesis: RBP3 and Anti-VEGF have differential protective profiles in preventing retinal dysfunctions induced by diabetes. Methods and Results: Recombinant human RBP3 (rhRBP3, 5ug/ml) and anti-VEGF (Avastin, 250mg/ml) inhibited VEGF-induced retinal vascular permeability (RVP) by 70% when intravitreal injections were given together in Lewis rats (P &amp;lt; 0.01) . After 2 months of diabetes induced by streptozotocin (STZ) , intravitreal injection of rhRBP3 and anti-VEGF for 3 days suppressed RVP by 64% and 53% (P &amp;lt; 0.01) in Lewis rats. This was accompanied by reductions of VEGF levels by both proteins. Electroretinogram (ERG) amplitudes of A wave, B wave, C wave were decreased in rats after 2 months of diabetes (P &amp;lt; 0.01) . rhRBP3 increased amplitudes of C wave (P &amp;lt; 0.01) , while anti-VEGF did not improve any waveforms. Furthermore, rhRBP3 decreased retinal mRNA expression of Cd11b and Tnfa (P =0.1) in diabetic rats. In cultured primary bovine Müller cells, rhRBP3 decreased mRNA expressions of Tnfa and Il-6 induced by high glucose (25mM) (P &amp;lt; 0.01) , whereas, anti-VEGF showed no effect. Metabolic function studies using Seahorse assays showed that isolated retina from intravitreal rhRBP3 treated rats exhibited reduced glycolysis rate in ECAR while anti-VEGF treatments had no effects. Conclusions: Both intravitreal anti-VEGF and RBP3 treatments normalized retinal vascular dysfunctions caused by diabetes. However, only RBP3 reversed abnormal neural-retinal dysfunctions and elevated inflammatory cytokines induced by hyperglycemia, possible by decreasing glucose uptake and glycolysis levels in retinal cells. Disclosure Q.Li: None. S.Onizuka: None. K.Park: None. H.Park: None. Q.Li: None. W.Fickweiler: None. J.Fu: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.

47-OR: Efficacy, Durability, and Safety of Faricimab in Diabetic Macular Edema: Two-Year Results from the Phase 3 YOSEMITE and RHINE Trials

Diabetic macular edema (DME) is a major cause of vision loss for people with diabetes. Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for DME; however, there is an unmet need for new strategies that address the multifactorial nature of DME, reduce treatment burden, and optimize patient outcomes. Angiopoietin-2 and VEGF-A synergistically drive vascular instability in DME; therefore, dual pathway inhibition with faricimab, the first bispecific antibody designed for intraocular use, may promote vascular stability and durable efficacy beyond current anti-VEGF therapies. YOSEMITE (NCT03622580) and RHINE (NCT03622593) were randomized, double-masked, active comparator-controlled, phase 3 trials designed to assess the efficacy, durability, and safety of faricimab in patients with DME (YOSEMITE, N = 940; RHINE, N = 951) . Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W) after 6 initial every-4-week (Q4W) doses, faricimab 6.0 mg per personalized treatment interval (PTI) after 4 initial Q4W doses, or aflibercept 2.0 mg Q8W after 5 initial Q4W doses. The PTI algorithm was a protocol-driven treat-and-extend regimen, with dosing intervals extended, maintained, or reduced (from Q4W up to every 16 weeks [Q16W]) based on prespecified vision and anatomic criteria. Efficacy and safety endpoints were assessed at Q4W study visits through week 100. At 1 year, faricimab Q8W or per PTI offered durable vision gains that were noninferior to aflibercept Q8W and were achieved with Q16W dosing in &amp;gt; 50% of patients in the PTI arms. Faricimab Q8W or per PTI demonstrated anatomic improvements versus aflibercept Q8W and was well tolerated, with low rates of intraocular inflammation. Year 2 results from YOSEMITE/RHINE will be presented at the meeting, and will examine whether early vision gains, anatomic improvements, and extended (up to Q16W) dosing with faricimab are maintained over 2 years. Disclosure C.J. Danzig: Advisory Panel; Genentech, Inc. Consultant; Adverum Biotechnologies, Genentech, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc. Research Support; Adverum Biotechnologies, Genentech, Inc., Kodiak Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation. J.A. Wells: Advisory Panel; Genentech, Inc. Research Support; Adverum, Alimera, Bayer AG, DRCR Retina Network, Genentech, Inc., Gyroscope, Iveric, Kodiak, Lowy Medical institute, Regeneron Pharmaceuticals Inc. D. Eichenbaum: Consultant; Genentech, Inc., Regeneron Pharmaceuticals Inc. Research Support; Bayer AG, Genentech, Inc., Regeneron Pharmaceuticals Inc. Speaker's Bureau; Bayer AG, Genentech, Inc. J.I. Lim: Consultant; Cognition, Eyenuk, Genentech, Inc., Iveric Bio, Novartis AG, Quark, Santen, Luxa, Veridian, Aura, Unity. Research Support; Aldeyra, Chengdu Pharmaceuticals, Regeneron Pharmaceuticals Inc., Stealth, NGM. K. Asik: None. Z. Haskova: Employee; Genentech, Inc. S. Mohan: None. D. Silverman: Employee; Roche Pharmaceuticals. Y. Tang: Employee; Genentech, Inc. H. Lin: Employee; Genentech, Inc. Funding F. Hoffmann-La Roche Ltd. (Basel, Switzerland)

Optimal Patient Adherence and Long-Term Treatment Outcomes of Neovascular Age-Related Macular Degeneration in Real-Life

Purpose To report on long-term real-life outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy in neovascular age-related macular degeneration (nAMD) with optimal patient adherence. Methods For this retrospective monocenter study, we identified 3217 eyes of 2793 patients that received a minimum of three intravitreal anti-VEGF injections for nAMD therapy between 2006 and 2014 at the University Eye Hospital Munich. From those, we included eyes with treatment-naïve nAMD, follow-up (FU) of ≥60 months and continuous adherence during FU. Primary measures were corrected visual acuity (VA), number of injections and visits as well as treatment regimen. Results We included 161 eyes of 125 patients with a mean FU of 8.0 ± 2.3 years. Mean VA at baseline was 60.1 letters (Snellen equivalent, 20/63). After the third year, mean VA declined constantly by 2–3 letters per year. After 5 and 8 years, 26.1% and 42.1% had lost at least 3 lines from baseline. Mean cumulative number of injections was 5.3 after the first year, and 23.9, 38.1, 48.5 after 5, 8, and 10 years. “Treat and extent” regimen with higher injection frequency correlated with better function. At time of last FU, 69.8% of eyes were under active treatment. Eyes with ≥70 letters at baseline correlated with better VA at the end of FU. Conclusions Despite optimal patient adherence, visual function declined progressively in real-life nAMD therapy over long-term. The highest impact on treatment success is given by an early treatment start with individual but intensive anti-VEGF therapy.

Sequential Short Interval Anti-VEGF for the Treatment of Stage 4 Retinopathy of Prematurity.

A 23-month-old girl born at 23 weeks' gestational age with a birth weight of 453 g and retinopathy of prematurity (ROP) stage 4A in 360° and plus disease in both eyes was treated in another institution with laser; her treatment was complicated with two cardiac arrests during the procedure. The patient was referred and treated at 31 weeks with repeated intravitreal bevacizumab injection in both eyes secondary to progressive ROP. Treatment with multiple anti-vascular endothelial growth factor (VEGF) therapy as monotherapy led to the resolution of a retinal detachment and full vascularization of the retina in both eyes. To the best of the authors' knowledge, this is the first description of a patient with stage 4A ROP treated solely with anti-VEGF after failed laser treatment that led to complete resolution of a retinal detachment without surgical intervention. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:159-163.].

Progression of retinal vascularization after intravitreal anti-vascular-endothelial growth factor therapy in retinopathy of prematurity

BackgroundAnti-vascular endothelial growth factor (Anti-VEGF) therapy is now considered as one of standard therapies in approaching infants with retinopathy of prematurity (ROP). The purpose of this study was to assess the time to full retinal vascularization in infants with ROP who were treated with intravitreal bevacizumab (IVB).MethodsThis retrospective cohort study evaluated premature infants with ROP who were treated with IVB between 2012 and 2019. Demographic and clinical data were collected from the medical records and analyzed. Main outcomes were defined as time to complete vascularization and time of zone shift.ResultsEight hundred sixty-five eyes from 441 patients were included. Average gestational age and birth weight were 28 ± 4 weeks and 1121 ± 624 g, respectively. Primary treatment failure and reactivation occurred in 35 eyes (4.0%) and 33 eyes (3.8%), respectively. Recurrent ROP occurred significantly more frequently in infants with pre-treatment zone 1 ROP compared to those with zone 2 ROP (7.6% versus 3%, p < 0.01). Patients with pre-treatment zone 2 reached zone 3 faster than those with pre-treatment zone 1 (142 ± 152 days versus 181 ± 174 days, p < 0.01); however, the time until full retinal vascularization did not significantly differ between the groups (p = 0.10).ConclusionThis study revealed that pre-treatment ROP zone was associated with ROP reactivation rate but not with time to full vascularization in those treated with IVB.Trial registration Retrospectively registered; IR.TUMS.FARABI.REC.1399.040

Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy

BackgroundPolypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis.ResultsWe cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 (KLF2) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples.ConclusionsHyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin.

Mental Status and Feasibility of an Intravitreal Ranibizumab Treat-and-Extend Regimen in Patients with Neovascular Age-Related Macular Degeneration.

Anti-vascular endothelial growth factor (VEGF) therapy is the first-choice treatment for neovascular age-related macular degeneration (nvAMD); however, patients often are burdened physically, financially, and mentally. We investigated the relationship between mental status and feasibility of an intravitreal ranibizumab treat-and-extend (TAE) regimen for nvAMD. In this prospective, multicenter study, 75 patients with nvAMD received ranibizumab intravitreally in a TAE regimen. After two monthly injections, the injection intervals were extended step-by-step to 6, 8, 12, and 16weeks in eyes with dry maculas on optical coherence tomography (OCT) and, if exudation persisted or relapsed, shortened by one step. The best corrected visual acuity (BCVA) measurement and OCT were performed at baseline and on the same days of the scheduled injections. At baseline, all patients completed a survey, the Hospital Anxiety and Depression Scale (HADS), regarding mental burden. At week52, patients on the TAE regimen for 1year completed the HADS and a questionnaire designated to assess treatment-associated mental status. Fifty-one patients (68%) completed the 1-year TAE regimen; 24 eyes (32%) discontinued the TAE regimen because of the rescue treatment, difficulty in completing clinical visits, or financial burden. In 51 eyes on the TAE regimen for 1year, the mean BCVAs improved from 64.3 letters at baseline to 71.6 letters at week52. The mean anxiety and depression scores on HADS decreased significantly (p < 0.01) after the 1-year treatment. Women tended to have higher anxiety scores, possibly associated with fear of injection and recurrence, while some men had higher depression scores potentially associated with financial burden, difficulty in completing clinical visits, and subsequent interruption of the TAE regimen especially in eyes with low treatment efficacy. A TAE regimen of intravitreal ranibizumab injections preserves vision in eyes with nvAMD and reduces mental burden associated with disease relapse. This clinical study was registered retrospectively on December22, 2014 with the ClinicalTrials.gov identifier NCT02321839.

A retrospective study assessing the factors associated with visual outcome in retinal vein occlusion patients after anti-VEGF therapy.

BackgroundRetinal vein occlusion (RVO) is one of the most frequent retinal vascular diseases. In this study, we aimed to investigate the predictive factors of visual outcome for RVO patients who underwent anti-vascular endothelial growth factor (VEGF) therapy.MethodsRVO patients who underwent anti-VEGF treatment were recruited in this study from January 2018 to June 2020. Clinical data and optical coherence tomography (OCT) parameters were retrospectively reviewed. Best-corrected visual acuity (BCVA) was examined at baseline and after anti-VEGF therapy. Predictive factors associated with visual outcome were assessed by logistic regression model. Treatment-related adverse events were also recorded.ResultsThe average logMAR BCVA was 0.91 at baseline and 0.70 at final examination (P = 0.003). Among 75 patients, 41 experienced visual improvement were categorized as group A, the remaining 34 patients without improved vision were categorized as group B. Patients in group A demonstrated better visual outcomes, including decreased logMAR BCVA (average logMAR BCVA: 0.53 in group A vs. 0.91 in group B, P < 0.001) and central retinal thickness (CRT) (average CRT: 230.88 µm in group A vs. 404.97 µm in group B, P < 0.001) after anti-VEGF treatment. Multivariable analysis showed that injection frequency (odds ratio [OR], 2.623; 95% confidence interval [CI], [1.282–5.366]), hypertension (odds ratio [OR], 0.189; 95% CI [0.044–0.811]), hyperlipemia (odds ratio [OR], 0.195; 95% CI [0.040–0.941]) and external limiting membrane (ELM) disruption (odds ratio [OR], 0.148; 95% CI [0.032–0.691]) were all significantly associated with the visual outcome of RVO patients who underwent anti-VEGF treatment. In general, anti-VEGF therapy was feasible for all RVO patients, though the response to anti-VEGF was suboptimal in certain patients. Prognostic factors including injection frequency, hypertension, hyperlipemia and ELM disruption may all be useful to provide predictive information of visual outcome of RVO patients in response to anti-VEGF treatment.

MiRNA Levels as a Biomarker for Anti-VEGF Response in Patients with Diabetic Macular Edema.

Background: The aim of this study was to investigate whether miRNA levels in the circulation could serve as a predictive biomarker for responsiveness to anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema. Methods: Whole blood samples were collected at baseline from 135 patients who were included in the BRDME study, a randomized controlled comparative trial of monthly bevacizumab or ranibizumab treatment for 6 months in patients with diabetic macular edema (Trialregister.nl, NTR3247). Best corrected visual acuity letter score (BCVA) and retinal central area thickness (CAT) were measured monthly during the 6-month follow-up. Levels of selected miRNAs were quantified. Results: Following linear regression analysis, the levels of four miRNAs were negatively associated with baseline CAT. Multivariable regression analysis confirmed this association for miR-181a. No associations with changes in CAT after 3 or 6 months of anti-VEGF treatment were found. In addition, no associations with miRNA levels with baseline BCVA or change in BCVA after 3 or 6 months of anti-VEGF treatment were found. Conclusions: Circulating miR-181a levels were negatively associated with CAT at baseline. However, no associations between miRNA levels and the response to anti-VEGF therapy were found.

Disease-modifying effects of ranibizumab for central retinal vein occlusion

PurposeTo identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes.MethodsA post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy.ResultsAt 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: − 1.17 [sham], − 2.37 [ranibizumab 0.3 mg], − 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups.ConclusionsRanibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.

De-novo multilayering in fibrovascular pigment epithelial detachment

This study describes the occurrence of multilayered pigment-epithelial detachment (MLPED) as a De-novo phenomenon (DN-MLPED) and compare the features with multi-layering secondary to chronic anti-vascular endothelial growth factor (anti-VEGF) therapy (s-MLPED). We did a retrospective evaluation of spectral-domain optical coherence tomography (SD-OCT) features, treatment-profile, and visual-acuity (VA) outcomes in eyes with MLPED. Out of 17 eyes with MLPED, 7 eyes had DN-MLPED and 10 eyes had s-MLPED. There was no significant difference in baseline and final VA between the groups. At the final visit, no significant visual improvement was noted in both the groups, although a possible trend towards an improvement was seen in DN-MLPED eyes while the s-MLPED demonstrated a declining trend (DN-MLPED—LogMAR-BCVA: Baseline = 0.79 [∼ 20/123] ± 0.91; Final = 0.76 [∼ 20/115] ± 0.73; p = 0.87; s-MLPED—LogMAR BCVA: Baseline = 0.43 [∼ 20/54] ± 0.68; Final = 0.94 [∼ 20/174] ± 0.71; p = 0.06). Moreover, after presentation, the median number of injections in DN-MLPED eyes were significantly lower compared to s-MLPED eyes (DN-MLPED:4; s-MLPED:12; p = 0.03) (Median follow-up: DN-MLPED = 26 months; s-MLPED = 54 months; p = 0.15). Subretinal hyperreflective-material (SHRM) deposition heralded the onset of multilayering and was seen to progress in all DN-PED eyes and 1/4 eyes of s-MLPED. To conclude, MLPED is a unique form of cicatrizing fibrovascular-PED which can evolve denovo too. Long-standing disease with intermittent or low-grade activity can potentially explain this unique phenomenon. With fewer anti-VEGF therapy, the de-novo MLPED eyes show more visual stability as compared to s-MLPED eyes.

Baseline Optical Coherence Tomography Parameters That May Influence 6 Months Treatment Outcome of Polypoidal Choroidal Vasculopathy Eyes with Combination Therapy: A Short-Term Pilot Study.

Although optical coherence tomography (OCT) parameters have assisted in the diagnosis of polypoidal choroidal vasculopathy (PCV), its potential to evaluate treatment outcomes has not been established. The purpose of this pilot study was to evaluate baseline OCT parameters that may influence treatment outcome in PCV eyes with combination therapy. In this single-centered, prospective study, patients were recruited with at least one treatment-naïve PCV eye and treated with combination therapy of intravitreal anti-vascular endothelial growth factor and photodynamic therapy. Best-corrected distance and near visual acuity (DVA and NVA), and contrast sensitivity (CS) were recorded at baseline and six months after treatment. OCT parameters were determined. Twenty-six eyes of 26 patients aged between 51 to 83 years were evaluated. In eyes that had disrupted external limiting membrane (ELM), photoreceptors inner and outer segment (IS-OS) junction at 1000 micron of fovea at baseline showed low mean visual functions after 6 months of treatment. Eyes with foveal sub-retinal fluid (SRF) and polyp at central 1000 micron of fovea at baseline showed significantly worse DVA and CS after six months. Thus, the presence of foveal SRF, foveal polyp, disrupted ELM, and IS-OS junction at baseline significantly influenced the six months’ visual outcome in PCV eyes treated with combination therapy.

A Prospective Review of Patients Receiving Intravitreal Anti-VEGF: How are we doing during the SARS-Cov-2 Pandemic?

Objective: During the SARS-CoV-2 pandemic, service provision of Anti- Vascular Endothelial Growth Factor (anti-VEGF) therapy is continued to prevent severe visual loss. As the majority of the patients requiring intravitreal anti- VEGF are elderly and vulnerable, we aim to assess the safety and efficacy of the delivery of anti-VEGF therapy. Method: A prospective data collection of 337 patients who attended the nurse led injection clinics in the UK during the lockdown period from 30 March 2020 to 1 June 2020. A follow up of all of the attended patients was conducted to assess for diagnosis of SARS-CoV-2. Results: 182 (54%) were female and 155 (46%) male. Majority (95%) were Caucasian and 5% were Asian ethnicity. The indication for anti-VEGF injection include wet age related macular degeneration (wet AMD) (70.9%), Diabetic Macular Oedema (DMO) (17.2%), and Retinal Vein Occlusion (RVO) (11.9%). Mean age was 78.84±9.76 for wet AMD, 67.63±3.26 for RVO and 59.28±14.54 for DMO. More wet AMD patients reported subjective deterioration of vision compared to RVO and DMO (40.2% vs. 37.5% vs. 22.4%) [P=0.04]. Chronic Obstructive Pulmonary Disease (COPD) is more common in the wet AMD group as compared to other groups (P=0.03). Five patients from the study group were tested for SARS-CoV-2, none were positive. Conclusion: Delivery of anti-VEGF therapy is safe with the current precautionary measures despite caring for a vulnerable group of patients. Majority of the wet AMD patients are continuing to attend intravitreal injection appointments.

Nanotechnology: revolutionizing the delivery of drugs to treat age-related macular degeneration

ABSTRACT Introduction: Age-related macular degeneration (AMD) is a progressive retinal disease that degrades the eye’s ability to grasp visual acuity. The antivascular endothelial growth factor (VEGF) therapies have made significant strides in improving the quality of life, and there is a continued opportunity to improve delivery, outcomes, and patient convenience and compliance. The treatments available could gain better clinical outcome from novel therapeutics through nanotechnology application. Areas covered: This review summarizes AMD biology and the pathophysiology of the disease along with the successes and limitations of available therapies. It further discusses the promising nanotechnology modalities that could become the cornerstone of future AMD research for improving delivery and reducing frequency of administration thus, enabling development of novel therapeutics. Expert opinion: The robust translation from preclinical work to clinical outcome for AMD remains an unmet need. Continuing to investigate in deeper understanding of biology and advancing high-quality targets into the clinic in combination with the application of advanced nanotechnology to design patient-centric offerings for both dry and wet AMD is needed. Because of the lack of regulatory precedence, and challenging manufacturing and supply chain need, the future of nano-enabled technologies is challenging but presents exciting treatment options for AMD.

Gaining insight on mitigation of rubeosis iridis by UPARANT in a mouse model associated with proliferative retinopathy

Proliferative retinopathies (PR) lead to an increase in neovascularization and inflammation factors, at times culminating in pathologic rubeosis iridis (RI). In mice, uveal puncture combined with injection of hypoxia-conditioned media mimics RI associated with proliferative retinopathies. Here, we investigated the effects of the urokinase plasminogen activator receptor (uPAR) antagonist—UPARANT—on the angiogenic and inflammatory processes that are dysregulated in this model. In addition, the effects of UPARANT were compared with those of anti-vascular endothelial growth factor (VEGF) therapies. Administration of UPARANT promptly decreased iris vasculature, while anti-VEGF effects were slower and less pronounced. Immunoblot and qPCR analysis suggested that UPARANT acts predominantly by reducing the upregulated inflammatory and extracellular matrix degradation responses. UPARANT appears to be more effective in comparison to anti-VEGF in the treatment of RI associated with PR in the murine model, by modulating multiple uPAR-associated signaling pathways. Furthermore, UPARANT effectiveness was maintained when systemically administered, which could open to novel improved therapies for proliferative ocular diseases, particularly those associated with PR.Key messages• Further evidence of UPARANT effectiveness in normalizing pathological iris neovascularization.• Both systemic and local administration of UPARANT reduce iris neovascularization in a model associated with proliferative retinopathies.• In the mouse models of rubeosis iridis associated with proliferative retinopathy, UPARANT displays stronger effects when compared with anti-vascular endothelial growth factor regimen.

Abstract 6331: Cloaking VEGF in small extracellular vesicles as a cause of adaptive resistance to anti-VEGF therapy

Abstract Despite the wide use of anti-vascular endothelial growth factor (VEGF) therapy (AVT) for many solid cancers, most of them become resistant to such therapy, resulting in progressive disease. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to AVT are needed. Small extracellular vesicles (small EVs, with a size of &amp;lt;200 nm) have been extensively studied as crucial intercellular messengers by delivering DNA, RNA, and proteins to recipient cells. We hypothesized that the packaging of angiogenic factors, especially VEGF, into small EVs could cause adaptive resistance to AVT by evading recognition by therapeutic antiboides. In this study, we carried out a series of in vitro (immunoblot analysis, flow cytometry, tube formation, and immunofluorescence staining) and in vivo (subcutaneous mouse models and Matrigel plug angiogenesis assay) experiments to determine the roles of small EVs in AVT resistance. We found that cancer-derived small EVs increasingly package VEGF and other factors in response to AVT. Further studies showed that bevacizumab cannot recognize the VEGF packaged inside small EVs (eVEGF) and eVEGF was protected from being neutralized by bevacizumab. Notably, eVEGF was transferred to endothelial cells, triggered intracrine signaling, and subsequently increased the number of tubes formed in an in vitro angiogenesis assay. In addition, VEGF was present at higher levels in serum small EVs in mouse models of adaptive resistance of ovarian cancer to bevacizumab than in models of sensitivity to it. Ovarian cancer cell-derived eVEGF increased tumor growth despite treatment with bevacizumab. Collectively, our data provide a new mechanism whereby eVEGF evades recognition by therapeutic antibodies and promotes tumor angiogenesis and progression. These findings have implications for biomarkers and new therapeutic strategies for ovarian cancer therapy. Citation Format: Shaolin Ma, Lingegowda S. Mangala, Wen Hu, Emine Bayaktar, Wei Hu, Nicholas B. Jennings, Robert L. Coleman, Gabriel Lopez-Berestein, Anil K. Sood. Cloaking VEGF in small extracellular vesicles as a cause of adaptive resistance to anti-VEGF therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6331.

The Efficacy of Conbercept in Polypoidal Choroidal Vasculopathy: A Systematic Review.

Methods Thirty studies with 1308 eyes were identified and included in this study. The primary outcome measures were best-corrected visual acuity (BCVA), and secondary outcomes were optical coherence tomography characteristics and polyp regression rates. The pooled results were calculated by the random-effect or fixed-effect model according to the heterogeneity of the data. Results Despite a large standard deviation in means (SMD) improvement for BCVA and central retinal thickness (CRT) in the conbercept group, there was no statistically significant difference in the other outcomes compared to ranibizumab and aflibercept. However, there was a greater polyp regression rate in the conbercept group at 12 months. Conclusions This systematic review indicates that conbercept may achieve similar BCVA and CRT improvements as ranibizumab and aflibercept, with a superior rate of polyp regression at 12 months.

Profiling neovascular age-related macular degeneration choroidal neovascularization lesion response to anti-vascular endothelial growth factor therapy using SSOCTA.

PurposeTo identify the changes in distinct vascular parameters of choroidal neovascularization (CNV) in eyes with treatment‐naïve neovascular age‐related macular degeneration (nAMD) during the primary response to anti‐VEGF therapy using aflibercept.MethodsPatients were prospectively followed during the first 3 months according to a standardized protocol with mandatory visits at days 7 and 14 after each anti‐VEGF treatment up to day 90. Fourteen eyes were seen in addition at days 1 and 3 post‐initial injection. Aflibercept was administered at baseline (BL), day 30 and 60. 6 × 6mm SSOCTA (PlexElite, Zeiss) images were acquired. Using the semi‐automated AngioTool, CNV area, vessel area, vessel density (VD), the number of junctions, junctions density, total vessel length, average vessel length, total number of endpoints and lacunarity were assessed.ResultsThirty‐two consecutive patients presenting with treatment‐naïve, SSOCTA‐positive CNV lesions were included. Close follow‐up showed a characteristic neovascular response curve with a dynamic decrease in lesion size within days and a reactive increase following 2 weeks after initial treatment. An undulating pattern was seen for all neovascular parameters except for vascular density, with variable statistical significance. Due to a flattening of the therapeutic response as early as after the second treatment, CNV lesion size and most of the related parameters had an increase in activity above baseline values at the end of the loading phase. Lesion size was the leading feature of reactivation by a mean increase of 19.3% after three monthly aflibercept injections. Subgroup analysis based on lesion size revealed a significant correlation between best‐corrected visual acuity and quantitative change in lesion size over time, but not baseline size.ConclusionsUsing SSOCTA, a morphologic neovascular response pattern can be identified in anti‐VEGF treatment of CNV. A synchronized early decrease and consecutive reactivation in a large spectrum of neovascular biomarkers including size and internal structure are visualized in a qualitative and quantitative manner. SSOCTA analyses allow new insights in CNV morphology changes and therapeutic response.