Anti-vascular Endothelial Growth Factor Agents Research Articles

The impact of laboratory findings and optical coherence tomography biomarkers on response to intravitreal anti-VEGF treatment in patients with retinal vein occlusion.

To investigate potential laboratory and imaging biomarkers as treatment response predictors to intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents in patients with retinal vein occlusion (RVO). Participants in this prospective study were 53 patients with treatment naïve macular edema secondary to RVO, treated with intravitreal anti-VEGF agents and followed-up for 12months. At baseline, all participants underwent best-corrected visual acuity measurement, dilated fundoscopy, optical coherence tomography and fluorescein angiography (FFA), while full blood count and biochemical analysis of various parameters was also performed. At month 12, treatment response was examined and classified as "favorable" or "non-response". Potential associations between laboratory/imaging biomarkers and treatment response were assessed. Univariate analysis showed that "favorable" response at month 12 after initiation of anti-VEGF treatment was correlated with baseline central subfield thickness (CST) < 464μm (p < 0.001), absence of subretinal fluid (p = 0.004), absence of hyperreflective foci (HF) (p = 0.004), intact ellipsoid zone (EZ) and external limiting membrane (ELM) (p < 0.001 and p = 0.001, respectively), absence of epiretinal membrane (ERM) (p = 0.020) and absence of macular ischemia on FFA (p < 0.001), while increased monocytes-to-lymphocytes ratio was also associated with "favorable" treatment response (p = 0.010). All other laboratory parameters did not reach statistical significance. However, at the multivariate analysis, EZ and ELM status, HF, macular ischemia and monocytes-to-lymphocytes ratio were found to be independent predictors of treatment response. Intact EZ and ELM, absence of HF, absence of macular ischemia and increased monocytes-to-lymphocytes ratio at baseline can predict "favorable" treatment response in patients with treatment naïve macular edema secondary to RVO.

KSI-301: an investigational anti-VEGF biopolymer conjugate for retinal diseases

Introduction KSI-301 is an intravitreal anti-vascular endothelial growth factor (VEGF) agent in clinical trials for the treatment of neovascular age-related macular degeneration (nAMD), diabetic retinopathy, diabetic macular edema (DME), and retinal vein occlusion (RVO). Its antibody-biopolymer conjugate structure is designed to decrease clearance from the eye and increase duration of effect. Areas covered This article briefly discusses the impact and mechanisms of nAMD, DME, and RVO and evaluates currently approved anti-VEGF therapies. It progresses to examine a new agent, KSI-301 and the results from numerous clinical trials in these disease areas. Expert opinion Despite varied results in the phase 2b/3 study for nAMD, there is potential for KSI-301 to serve as a durable therapy for VEGF-mediated retinal disorders. Ongoing phase 3 trials for nAMD, DME and RVO will provide additional evidence on its efficacy, duration and safety profiles.

Acute Syphilitic Posterior Placoid Chorioretinitis With Subfoveal Choroidal Neovascularization Managed With Anti-VEGF Therapy.

We describe the development and management of choroidal neovascularization (CNV) in a patient with acute syphilitic posterior placoid chorioretinitis (ASPPC). A retrospective case review is presented. A 66-year-old man presented with unilateral blurry vision. He had a history of systemic syphilis infection twice, the last diagnosed 15 years before presentation and treated with intravenous ceftriaxone, resulting in seroreversion of an initially positive rapid plasma reagin (RPR). Examination revealed ASPPC with subfoveal CNV. Repeat testing revealed an RPR titer of 1:16 384. He was treated with 6 monthly intravitreal injections of bevacizumab and systemic antibiotics, resulting in resolution of his ASPPC and regression of his CNV. CNV is a rare complication of ASPPC. Multimodal imaging can be useful to suggest the diagnosis, and prompt treatment with systemic antibiotics and intravitreal anti-vascular endothelial growth factor agents can lead to resolution of ASPPC and regression of CNV, respectively.

Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF).

The incidence of retinopathy of prematurity (ROP) continues to rise due to the improved survival of very low birth weight infants in developed countries. This epidemic is also fueled by increased survival of preterm babies with variable use of oxygen and a lack of ROP awareness and screening services in resource-limited regions. Improvements in technology and a basic understanding of the disease pathophysiology have changed the way we screen and manage ROP, educate providers and patients, and improve ROP awareness. Advancements in imaging techniques, expansion of telemedicine services, and the potential for artificial intelligence-assisted ROP screening programs have created opportunities to improve ROP care in areas with a shortage of ophthalmologists trained in ROP. To address the gap in provider knowledge regarding ROP, the Global Education Network for Retinopathy of Prematurity (GEN-ROP) created a web-based tele-education training module that can be used to educate all providers involved in ROP, including non-physician ROP screeners. Over the past 50 years, the treatment of severe ROP has evolved from limited treatment modalities to cryotherapy and laser photocoagulation. More recently, there has been growing evidence to support the use of anti-vascular endothelial growth factor (VEGF) agents for the treatment of severe ROP. However, VEGF is known to be important in organogenesis and microvascular maintenance, and given that intravitreal anti-VEGF treatment can result in systemic VEGF suppression over a period of at least 1-12 weeks, there are concerns regarding adverse effects and long-term ocular and systemic developmental consequences of anti-VEGF therapy. Future research in ophthalmology to address the growing burden of ROP should focus on cost-effective fundus imaging devices, implementation of artificial intelligence platforms, updated treatment algorithms with optimal use of anti-VEGF and careful investigation of its long-term effects, and surgical options in advanced ROP. Addressing these unmet needs will aid the global effort against the ROP epidemic and optimize our understanding and treatment of this blinding disease.

Aortic stiffness and systemic inflammation changes predict clinical response to intravitreal anti-vascular endothelial growth factor therapy in patients with age-related macular degeneration.

Aortic stiffness and systemic inflammation are predictors of cardiovascular risk. Anti-vascular endothelial growth factor agents (anti-VEGF), injected intravitreally, can reverse the course of exudate age-related macular degeneration (AMD). We sought to investigate the association of changes in aortic stiffness and systemic inflammation with response to anti-VEGF therapy. 54 patients (mean age: 76 ± 10 years) with AMD received two consecutive monthly intravitreal injections of ranibizumab (0.5 mg). The primary outcome measure was change in carotid-femoral pulse wave velocity (PWV) from baseline to 1 month after the second injection. Secondary endpoint was the change in serum high sensitivity interleukin-6 (hsIL-6) levels. Ranibizumab caused a decrease of PWV after the first (by 0.36 ± 1.4 m/s) and the second injection (by 0.31 ± 1.4 m/s) and remained decreased 1 month after the second injection (overall P < 0.05). PWV decreased significantly in good responders (according to clinical criteria and fundus findings, P = 0.004), whereas it increased numerically in poor responders (P = 0.21) over the study period. In responders, hsIL-6 decreased after the first injection and remained decreased 1 month after the second injection (by 0.63 ± 0.35 pg/ml, overall P = 0.02). PWV (P = 0.005) and hsIL-6 (P = 0.042) were independent predictors of improvement after adjusting for age and presence of hypertension and diabetes. The decrease in PWV through the whole study period was positively correlated with the reduction in hsIL-6 (r = 0.36, P < 0.01). Intravitreal ranibizumab injections lead to a decrease in PWV and hsIL-6. Both parameters predict clinical improvement and may aid to improving treatment targeting and hence therapeutic outcome in patients with AMD.

Long term results of three anti-vascular endothelial growth factor agents in pachychoroid neovasculopathy

Purpose To assess morphological changes and visual results in eyes with pachychoroid neovasculopathy (PNV) that underwent different intravitreal anti-vascular endothelial growth factor (VEGF) agents. Materials and methods This is a retrospective, observational, comparative study that included 76 PNV eyes in 76 patients that were allocated to three groups according to the monotherapy injection procedure, as follows: the intravitreal bevacizumab (IVB) group, intravitreal ranibizumab (IVR) group, and intravitreal aflibercept (IVA) group. Central macular thickness (CMT), best-corrected visual acuity (BCVA), and subfoveal choroidal thickness (SFCT) were measured at baseline, after treatment 1st month, 3rd month, 6th month, and 12th month, and at the final post-treatment examination. Results Mean age of the patients was 57.31 ± 5.91 years (range: 34–67 years). The mean duration of follow-up was 31.50 ± 12.91 months (range: 13–60 months). The IVB group included 30 eyes, the IVR group included 22 eyes, and the IVA group included 24 eyes. There weren’t any significant differences in BCVA changes between the groups at any post-baseline measurement time point. Although CMT did not change significantly in the IVB group from baseline to the final follow-up visit (baseline: 376.33 ± 86.31 µm; final visit: 340.80 ± 122.70 µm) (p = 0.172), CMT did change significantly in the IVA group (baseline: 383.41 ± 131.83 µm; final visit: 297.33 ± 103.81 µm) (p = 0.029) and IVR group (baseline: 379.18 ± 97.93 µm; final visit: 335.72 ± 111.45 µm) (p = 0.041). SFCT decreased significantly in the IVR and IVA groups (p = 0.015 and p < 0.001, respectively). The mean number of injections was 12.06 ± 4.72 (range: 6–20) in the IVB group, 11.81 ± 3.31(range: 7–17) in the IVR group, and 7.16 ± 3.15 (range: 4–13) in the IVA group (p = 0.004). Conclusion All three anti-VEGFs were effective in terms of visual results in patients with PNV. Patients treated with IVA required fewer injections than those treated with IVB or IVR. Furthermore, IVR and IVA treatment significantly decreased SFCT, whereas IVB did not.

RELATIONSHIP BETWEEN CHOROIDAL FINDINGS AND GROWTH FACTORS, CYTOKINES, AND OTHER INFLAMMATORY MEDIATORS AFTER INTRAVITREAL RANIBIZUMAB INJECTION IN PATIENTS WITH MACULAR EDEMA SECONDARY TO BRANCH RETINAL VEIN OCCLUSION.

To examine possible associations between subfoveal choroidal thickness (SCT), choroidal blood flow, aqueous flare value, and aqueous humor levels of multiple growth factors, cytokines, and other inflammatory mediators in patients with branch retinal vein occlusion and macular edema who received antivascular endothelial growth factor (anti-VEGF) therapy. We recruited 65 patients with macular edema due to branch retinal vein occlusion who received intravitreal ranibizumab injection and measured aqueous levels of eight factors by the suspension array method. Furthermore, we evaluated choroidal blood flows by laser speckle flowgraphy and quantified them as the mean blur rate and measured aqueous flare values using a laser flare meter and SCT and central macular thickness by optical coherence tomography. At 1 month after intravitreal ranibizumab injection, central macular thickness was significantly improved and SCT, choroidal mean blur rate, and aqueous flare value were significantly decreased. SCT was significantly correlated with vascular endothelial growth factor and placental growth factor, and the change in both SCT and central macular thickness was significantly correlated with the change in aqueous flare value. However, only SCT was significantly negatively correlated with the aqueous flare value. Growth factors seem to play a role in SCT. In macular edema with branch retinal vein occlusion, antivascular endothelial growth factor agents may decrease SCT by reducing inflammation.

OUTCOME OF THE MANAGEMENT OF AGGRESSIVE RETINOPATHY OF PREMATURITY (A-ROP)

Objective: To compare the efcacy and safety between laser therapy and anti-vascular endothelial growth factor (VEGF) agents for aggressive retinopathy of prematurity (A-ROP). Acomparative study for laser, anti VEGF with laser and anti-VEGF mono therapy forPatients and methods: A-ROP treatment. Study period was 2016 to 2020 at BIRDEM General Hospital. We included fteen A-ROP babies with thirty eyes. Ten eyes treated with laser, ten eyes treated with anti-VEGF with laser and ten eyes treated with anti-VEGF. We used Bevacizumab as anti-VEGF. We compared efcacy, safety, complication, retreatment between these three groups. Complication incidences were signicantly higher inResult: laser therapy group. 20% of infants' needs retreatments with laser therapy more than two sessions. In anti-VEGF and laser therapy group, 6.7% of infants need retreatment and in anti-VEGF group-1 3.3% infants need retreatment. P-value was 0.005 which is signicant. Development of myopia is signicantly higher in laser therapy group (Group-3). About 100% infants' developed myopia. In Group-2 30% infants' developed myopia. In Group-1 no infants developed myopia. P-value was highly signicant 0.01. This analysis outcome indicates anti-VEGF agents are asConclusion: effective as laser treatment and safer than laser. The degree of myopia in A-ROP in laser group is higher than anti-VEGF mono therapy group. The decreased incidence of early unfavorable refractive and functional outcomes in the IVB group compared with the laser group showed a potential benet for patients treated with Intravitreal Bevacizumab (IVB).

Vascular endothelial growth factor-A level in human breast milk after intravitreal injection of ranibizumab: a case report

BackgroundRanibizumab is one of intravitreal anti-vascular endothelial growth factor agents. It is applied in the treatments of choroidal neovascularization, age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. Preliminary evidence suggests that intravitreal ranibizumab may enter the plasma and human breast milk in very low-level concentration. As a precaution, breastfeeding is not recommended during the treatment of intravitreal injection of ranibizumab. There are limited data regarding the change of anti-vascular endothelial growth factor concentration in human breast milk after intravitreal injection of ranibizumab, especially in the first 24 h after injection. The purpose of this report is to analyse the concentration change of vascular endothelial growth factor-A in human breast milk with time, in the short term after intravitreal injection of ranibizumab.Case presentationIn June 2018, a 30-year-old patient breastfeeding a six-month-old baby was diagnosed with choroidal neovascularization of left eye in Eye Hospital of Wenzhou Medical University. She received four administrations of 0.5 mg intravitreal injection of ranibizumab of the left eye, and breast milk was collected just before the injection, and 1–3, 6, 12, 24, 48, and 72 h after intravitreal injection, and assessed for vascular endothelial growth factor-A concentration. The change in vascular endothelial growth factor-A concentration in human breast milk showed the same trend after each injection, decreasing significantly within 6–12 h (about 20–30% lower), and increasing to pre-injection level by 24 h after injection.ConclusionsThe concentration of vascular endothelial growth factor-A in human breast milk of a mother who continues lactating dropped initially and rose to pre-injection level about 24 h after intravitreal injection of ranibizumab. The data may offer more information to evaluate the impact of anti-vascular endothelial growth factor agent intravitreal injection of lactating mothers and their breastfed infants.

Sub-Tenon's capsule triamcinolone acetonide injection to prevent brolucizumab-associated intraocular inflammation.

To investigate the efficacy of sub-Tenon's capsule triamcinolone acetonide (STTA) injections for preventing development of intraocular inflammation (IOI) related to intravitreal injection (IVI) of brolucizumab for neovascular age-related macular degeneration (nAMD). Consecutive patients with nAMD treated with brolucizumab IVIs were studied retrospectively. All eyes treated with brolucizumab in the clinic were switched from another anti-vascular endothelial growth factor agent. After the fourth case of IOI related to brolucizumab IVI, all eyes treated with brolucizumab received a STTA injection. The patients were divided into two groups: brolucizumab alone and brolucizumab combined with a STTA injection. Forty-four eyes (44 patients) treated with at least one brolucizumab IVI were studied: 14 eyes received brolucizumab IVI alone and 30 eyes received the combination therapy. IOI related to brolucizumab IVIs developed in four (28.6%) of 14 eyes in the brolucizumab group; IOI was severe in one eye, moderate in two eyes, and mild in one eye according to the HAWK and HARRIER trial definition; IOI did not develop in the 30 eyes that received combination therapy, the difference of which reached significance (p = 0.012). Regarding combination therapy, the intraocular pressure in three (10%) eyes increased to 22 to about 26mmHg after the STTA injection and returned to normal range within 2months without medication; no cataracts developed during this short mean follow-up period follow-up period of 7.1 ± 0.4months. The results indicated the possible preventative effect of a STTA injection on development of brolucizumab-associated IOI.

CHARACTERIZING COVID-19-RELATED RETINAL VASCULAR OCCLUSIONS: A Case Series and Review of the Literature.

To describe clinical and ophthalmologic features and outcomes of patients with coronavirus disease-19 with retinal vascular occlusions. Retrospective multicenter case series and PubMed review of cases reported from March 2020 to September 2021. Outcome measures are as follows: type of occlusion, treatments, best-corrected visual acuity, and central macular thickness on optical coherence tomography. Thirty-nine patients were identified. Fifteen patients with a median age of 39 (30-67) years were included in the multicenter study. Vascular occlusions included central retinal vein occlusion (12 eyes), branch retinal vein occlusion (4 eyes), and central retinal artery occlusion (2 eyes). Three cases were bilateral. Baseline best-corrected visual acuity was 20/45 (no light perception-20/20). Baseline central macular thickness was 348.64 (±83) μm. Nine eyes received anti-vascular endothelial growth factor agents, dexamethasone intravitreal implant, or both. Final best-corrected visual acuity was 20/25 (no light perception-20/20), and central macular thickness was 273.7 ± 68 μm (follow-up of 19.6 ± 6 weeks). Among the 24 cases from the literature review, retinal vein occlusion was the predominant lesion. Clinical characteristics and outcomes were similar to those found in our series. Coronavirus disease-19-associated retinal vascular occlusions tend to occur in individuals younger than 60 years. Retinal vein occlusion is the most frequent occlusive event, and outcomes are favorable in most cases.

The Quantification and Impact of Persistent Retinal Fluid Compartments on Best-Corrected Visual Acuity of Patients With Retinal Vein Occlusion

To evaluate the impact of persistent intraretinal fluid (IRF) and subretinal fluid (SRF) on best visual acuity (BVA) of patients with retinal vein occlusions (RVOs). This retrospective cohort study observed 92 treatment-naïve patients with RVO during 12 months of treatment with anti-vascular endothelial growth factor agents. Deep learning was used to quantify IRF and SRF volumes, and linear mixed effects regression modeled the impact on BVA. Average IRF volume declined -923.1 ± 2,382.5 nL from baseline to 12 months (P < .001). Average SRF volume declined -35.4 ± 223.4 nL from baseline to 12 months (P = .139). linear mixed effects regression modeling disclosed IRF≥ 1,616 nL at all time points predicted a -10.38 letter loss at 12 months (95% CI, -14.58 to -5.9 letters; P < .001). A similar relationship was not found for SRF. Persistent IRF may be an important prognostic biomarker for BVA outcomes in real-world patients with RVO. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:139-147.].

Neovascular Age-Related Macular Degeneration (nAMD): A Review of Emerging Treatment Options.

Neovascular age-related macular degeneration (nAMD) is a common world-wide cause of visual loss. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are an effective means to treat nAMD and reduce its impact on vision compared to either sham treatment or photodynamic therapy. Currently, the approved anti-VEGF drugs include ranibizumab, aflibercept and brolucizumab. In addition, bevacizumab, used as an off-label drug, and has been shown to be effective in treating nAMD. While anti-VEGF agents are effective, its limitations include the requirement for frequent, often monthly injections, and the need for long-term treatment of nAMD. These present significant burdens on the healthcare system and on the patients. In addition, reviews of patients with nAMD treated with anti-VEGF have reported deterioration of vision over time with progression of geographic atrophy. These limitations are partly addressed by exploring different treatment regimens that reduce the frequency of treatments. Newer anti-VEGF drugs have been shown in Phase III clinical trials to have injection intervals as long as 12 or even 16 weeks for a proportion of patients. There is research on newer drugs that affect other pathways, such as the angiopoietin pathway, which may impact nAMD by extending the treatment interval and reducing the burden of treatment. Other measures include the use of sustained-release implants that release the drug regularly over a period of time, and can be refilled periodically, as well as hydrogel platforms that serve to release the drug. The use of biosimilars will also serve to reduce the cost of treatment for nAMD. A new frontier of gene therapy, primarily targeting genes involved in the transduction of retinal cells to produce anti-VEGF proteins intraocularly, also opens a new avenue of therapeutic approaches that can be used for treatment. This review paper will discuss both current treatment options and the newer treatments under development.

Anti-PD-1 Monoclonal Antibody Combined With Anti-VEGF Agent Is Safe and Effective in Patients With Recurrent/Metastatic Head and Neck Squamous Cancer as Second-Line or Beyond Treatment.

BackgroundNumerous preclinical studies have revealed the complex regulatory mechanisms between anti-angiogenesis and immune inhibition in the tumor immune microenvironment and have proposed the efficacy of combined immunotherapy and anti-angiogenic treatment. Moreover, the combination strategy had been confirmed in a number of clinical trials. In this study, we aimed to evaluate the safety and efficacy of this combination strategy in recurrent/metastatic head and neck squamous cell carcinoma.MethodsIn this real-world study, 43 patients who received the combination of programmed cell death protein 1 (PD-1) inhibitors and anti-vascular endothelial growth factor (VEGF) agents in Zhejiang cancer hospitals between March 2019 and December 2020 were reviewed. Clinical characteristics and follow-up data were collected, and the preliminary efficacy and safety of the combination therapy were assessed.ResultsThe median follow-up time was 12.4 months (range, 3.7-25.3 months), and the follow-up rate was 100%. The median duration of exposure was 9.5 months. Thirty-seven patients (86.0%) reported treatment-related adverse events (TRAEs) of any grade. The most frequently reported events were fatigue, decreased appetite, and hypertension. Grade 3 TRAEs occurred in 8 patients (18.6%), and no grade 4 or 5 TRAEs occurred. Twenty-four patients (55.9%) had an overall response to treatment: 6 (14.0%) had a complete response and 18 (41.9%) had a partial response. In addition, 5 (11.6%) patients had stable disease, and the disease control rate 12 was 67.4%. The median time to response was 1.6 months (range, 1.1-2.8 months). The median progression-free survival (PFS) was not reached, and the 1-year PFS rate was 69.1%. The 1-year overall survival (OS) rate was 87.7%. Patients with primary tumors located in the nasopharynx had better OS than those with tumors outside the nasopharynx. ECOG PS were related to PFS; patients with an ECOG PS of 0 had a slight survival advantage.ConclusionThe combination strategy of anti–PD-1 monoclonal antibodies and anti-VEGF agents was tolerable in patients with recurrent/metastatic head and neck cancer. This treatment exhibited antitumor potential despite the heavily pretreated population.

Comparison of Fluorescein Angiography Findings in Stage 3 Retinopathy of Prematurity in Zone II Treated With or Without Anti-VEGF.

To define late-stage fluorescein angiography (FA) findings in patients who received anti-vascular endothelial growth factor (VEGF) agents (intravitreal bevacizumab or aflibercept) as a treatment for stage 3 retinopathy of prematurity (ROP) in zone II. We also compared the findings of untreated eyes. Infants with a history of ROP who underwent fluorescein angiography were evaluated retrospectively. The patients were divided into 2 groups: those who received anti-VEGF treatment and those who regressed spontaneously without treatment. Vascular abnormalities, such as vascular leakage, shunts at the vascular-avascular junction, periarteriolar areas with hypoperfusion, fine branching and blunt termination of the vessels and, were recorded. Angiography evaluations revealed leakage in the eyes of 27.69% of the infants in the anti-VEGF-treated group and in 21.7% of the untreated group (p = .638). Among the abnormal vascular findings in the peripheral retina, the ratios of fine branching and blunt termination, numbers of shunts along the vascular-avascular junction, and sizes of periarteriolar areas of hypoperfusion were significantly larger in the untreated group than in the treated group (p < .05; p < .01). The gestational ages and birth weights were significantly lower (p ≤ .05) in infants with vascular findings in both groups. Vascular abnormalities in the peripheral retina are likely due to the ROP itself. Although these abnormalities were detected by FA imaging in both treated and untreated infants with ROP, they were significantly less frequent in patients treated with anti-VEGF, indicating that anti-VEGF treatments have a partially positive effect on the retinal vascularization process.

A randomized, open-label, multicenter study of switching to brolucizumab with or without a loading dose for patients with suboptimal anatomically controlled neovascular age-related macular degeneration—the FALCON study

BackgroundTreatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment.MethodsFALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability.ResultsFALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD.ConclusionsThe results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade.Trial registrationClinicaltrials.gov: NCT04679935, date of registration—22-Dec 2020; EUDRACT number: 2019–004763-53, date of registration—03 Dec 2019.

Efficacy of Intravitreal Injection of Filtered Modified Low-Dose Triamcinolone Acetonide and Ranibizumab on Pseudophakic Cystoid Macular Edema.

PurposeTo compare the visual and morphological effects between intravitreal injection of filtered modified 2 mg triamcinolone acetonide (TA) and 0. 5 mg ranibizumab in patients with pseudophakic cystoid macular edema (PCME).MethodsA retrospective, interventional study was conducted from January 2015 to February 2020 involving patients with PCME after uneventful cataract surgery. A total of 25 patients (25 eyes) with PCME received an intravitreal injection of 0.22 μm filtered modified 2 mg TA, while 15 patients (15 eyes) received 0.5 mg ranibizumab injection. Central macular thickness (CMT), best-corrected visual acuity (BCVA), intraocular pressure (IOP), times of repeated injections, and other side effects were observed at 2 weeks, 1 month, 3 months, and 6 months after injection; then, the data were compared with preinjection information in each group and between the two groups.ResultsBoth the TA and ranibizumab intravitreal injection can achieve improved BCVA and reduced CMT in patients with PCME (P < 0.05), with a trend toward greater improvement in the TA group, but the difference was only significant at 3 months (P < 0.05). IOP was in the normal range without any significant difference (P > 0.05). Thirty-three percent of patients in the ranibizumab group required repeated intravitreal injection compared to 4% in the TA group. Further stratified analysis showed that the better therapeutic effect of the TA group at 3 months after injection only existed in patients with diabetes mellitus (DM), while not in patients without DM. There was no repeat injection in the TA group and 12.5% in the ranibizumab group for patients without DM, while 16.7% in the TA group and 57.1% in the ranibizumab group required repeated injection for patients with DM, which had a significant difference (P < 0.05).ConclusionIntravitreal injection of filtered modified 2 mg TA is safe, effective, and an inexpensive alternative to antivascular endothelial growth factor (anti-VEGF) agents for patients with PCME, especially for patients concurrently with DM. A large number of clinical randomized controlled studies along with long-term follow-up observations are needed.

Mid-Term Impact of Anti-Vascular Endothelial Growth Factor Agents on Intraocular Pressure.

The effect of intraocular injections of anti-vascular endothelial growth factor (VEGF) on intraocular pressure (IOP) has not been clearly stated. We extracted data from the electronic health records at Dijon University Hospital of 750 patients who were unilaterally injected with anti-VEGF agents between March 2012 and March 2020. These were treatment-naïve patients who had received at least three injections of the same treatment (aflibercept, bevacizumab, or ranibizumab) in one eye only, and had IOP measurements before and after the injections. Fellow untreated eyes were used as comparators. A clinically significant IOP rise was determined as an IOP above 21 mmHg and an increase of at least 6 mmHg compared to baseline, or the need for IOP-lowering agents. We found an overall slight increase in IOP between treated and untreated eyes at 6 months (+0.67 ± 3.33 mmHg, 95% confidence interval 0.33–1.02, p < 0.001). Ranibizumab had a higher final IOP at 1 and 3 months. Age, sex, and the number of injections were not associated with IOP variation. Ranibizumab was associated with a higher rate of increase in clinically significant IOP at 6 months (p = 0.03). Our study confirms that anti-VEGF injections constitute a relatively safe treatment regarding their impact on IOP.

Hypothetical Switch of Anti-Vascular Endothelial Growth Factor in Neovascular Age-Related Macular Degeneration: An ARIES Post Hoc Analysis.

IntroductionSwitching to an alternative anti-vascular endothelial growth factor (anti-VEGF) agent has been suggested for patients with neovascular age-related macular degeneration (nAMD) who have a suboptimal response to initial therapy. However, post hoc analyses of some studies have shown that continuation of initial anti-VEGF therapy is, in many cases, associated with stable visual outcomes or gradual gains.MethodsThis ARIES (ClinicalTrials.gov Identifier: NCT02581891) post hoc analysis describes outcomes in patients with treatment-naïve nAMD receiving treat-and-extend intravitreal aflibercept (IVT-AFL) for 104 weeks, who were identified as meeting criteria for an early hypothetical switch. Patients were categorized retrospectively according to six criteria (presence of central intraretinal and/or subretinal fluid at week 8 or 24, with/without a next planned treatment interval ≤ 8 weeks, and with/without gains in best-corrected visual acuity [BCVA] ≤ 5 letters [with absolute BCVA < 70 letters]).ResultsHypothetical switch criteria were largely met due to the presence of central subretinal fluid rather than intraretinal fluid. Depending on the criterion, 8–46% of patients were considered to be hypothetical switchers. BCVA outcomes were not worse in the hypothetical switchers, irrespective of criteria. Using criteria of intraretinal/subretinal fluid at week 24 and a next planned treatment interval ≤ 8 weeks, mean changes in BCVA (letters) from baseline in hypothetical switchers and non-switchers were: + 6.1 (95% confidence interval [CI] 3.4, 8.8) and + 6.6 (95% CI 4.7, 8.6), respectively, at week 24; + 8.2 (95% CI 5.0, 11.3) and + 7.5 (95% CI 5.3, 9.7), respectively, at week 52; and + 5.7 (95% CI 1.3, 10.1) and + 3.4 (95% CI 0.1, 6.7), respectively, at week 104.ConclusionsIn newly diagnosed nAMD, there appears little rationale for early switching from IVT-AFL since, with continuous proactive treatment, comparable visual gains can be achieved by patients meeting hypothetical switch criteria compared with those who initially respond well on a treat-and-extend regimen. However, further prospective studies are needed.Trial registrationClinicalTrials.gov Identifier: NCT02581891.Video Summary Video summary of the ARIES Post Hoc Analysis “Hypothetical Switch of Anti-Vascular Endothelial Growth Factor in Neovascular Age-Related Macular Degeneration” (MP4 54283 KB)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40123-021-00448-w.

VEGF-Trap Modulates Retinal Inflammation in the Murine Oxygen-Induced Retinopathy (OIR) Model.

Anti-Vascular Endothelial Growth Factor (VEGF) agents are the first-line treatment for retinal neovascular diseases, which represent the most prevalent causes of acquired vision loss world-wide. VEGF-Trap (Aflibercept, AFL), a recombinant decoy receptor recognizing ligands of both VEGFR-1 and -2, was recently reported to be highly efficient in improving visual acuity and preserving retinal anatomy in individuals affected by diabetic macular edema. However, the precise molecular and cell biological mechanisms underlying the beneficial effects of this novel tool have yet to be elucidated. Using the mouse oxygen-induced retinopathy (OIR) model as a surrogate of retinopathies with sterile post-ischemic inflammation, such as late proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and diabetic macular edema (DME), we provide evidence that AFL modulates inflammation in response to hypoxia by regulating the morphology of microglial cells, a parameter commonly used as a proxy for changes in their activation state. We show that AFL administration during the hypoxic period of OIR leads to an increased number of ramified Iba1+ microglial cells/macrophages while subsequently limiting the accumulation of these cells in particular retinal layers. Our results suggest that, beyond its well-documented beneficial effects on microvascular regeneration, AFL might exert important modulatory effects on post-ischemic retinal inflammation.