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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Risk of transient vision loss after intravitreal aflibercept using vial-prepared vs. the novel prefilled syringe formulation.

Purpose: To compare the risk of transient vision loss (TVL) probably attributable to a severe intraocular pressure spike after intravitreal aflibercept application using the novel prefilled syringe (PFS) vs. the established vial system (VS). Methods: Datasets of the intravitreal injection service of the Ludwig Maximilians-University Munich and the Technical University Munich, Germany, were screened for documentation of TVL after intravitreal injection of aflibercept. The observation period included two full months prior to the introduction of the novel PFS and two months afterwards. TVL was defined as loss of perception of hand motion for a duration of >30 s. Results: Over a period of four months, 1720 intravitreal injections of aflibercept were administered in 672 patients. There were 842 injections with the old VS, and 878 injections using the novel PFS. Using the VS, TVL was noted during two injections (0.24%) in two patients, as compared to 11 cases of TVL (1.25%) in 10 patients with the PFS (p = 0.015). Using the PFS, patients had a 5.3-fold risk of TVL as compared to the VS (OR: 5.33; 95% CI: 1.2-24.1; p = 0.0298). Conclusion: There was a more than five-fold risk of TVL using the novel pre-filled aflibercept syringe as compared to the established vial system. During informed consent, this risk should be discussed.

Presumed Melanocytoma-Associated Choroidal Neovascular Membrane with Hemorrhage Successfully Treated with Intravitreal Aflibercept Injections.

A patient presented with melanocytoma and associated choroidal neovascular membrane with hemorrhage involving the macula. The patient was treated with monthly aflibercept (Eylea) injections with significant improvement of best corrected visual acuity. In this report, we explore the development of a choroidal neovascular membrane (CNVM) formation in a patient with melanocytoma and the effect of intravitreal aflibercept (Eylea) on disease course. Case report study used patient data obtained from examination and imaging. The patient was treated with monthly intravitreal aflibercept injections leading to complete resolution of CNVM and hemorrhage, with significant improvement of best corrected visual acuity. Awareness and proper monitoring for the sequelae of melanocytoma are important for early detection and prevention of visually threatening outcomes. In cases of melanocytoma-associated CNVM formation with large subretinal hemorrhage, intravitreal aflibercept can be an effective tool for inducing CNVM regression and allowing improvement of visual acuity.

Intravitreal sirolimus with adjunct aflibercept versus aflibercept monotherapy for persistent, exudative age-related macular degeneration: a pilot study.

BACKGROUND: To determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment. METHODS: This institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness. RESULTS: 20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 µm compared to 0.1 µm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension. CONCLUSION: There was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732899. Registered 11 March 2016, https://clinicaltrials.gov/ct2/show/NCT02732899 . This trial was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

Aflibercept Versus Bevacizumab as First-Line Therapy in Age-Related Macular Degeneration.

BACKGROUND: AMD (age-related macular degeneration) is the main cause of central vision loss in the population over 60 years old. AMD does not affect peripheral vision and complete blindness does not occur, instead, central vision is affected both for distance and for near. The purpose of this study is to evaluate the neovascular form of AMD treatment and compare ocular and systemic effects after intravitreal injection of aflibercept, respectively after bevacizumab when administered in comparable dosages and regimens. We conducted a retrospective, single-center study from June 2021 to December 2022 and enrolled 20 patients with neovascular AMD who had not received any prior treatment for this condition. We randomly assigned them to two groups of 10: group one received aflibercept and group two received bevacizumab as intravitreal injections under aseptic conditions. We excluded 2 patients who did not meet the criteria and ended up with two groups of 9 patients who received monocular treatment. We gave the patients 3 monthly injections of anti-VEGF agent and followed them up at 1 month, 3 months, and 9 months after the treatment. We assessed their visual acuity, intraocular pressure and OCT appearance at each follow-up visit. The primary outcome was visual acuity. All 18 patients included in the study reported an improvement in visual acuity after the intervention. When comparing the two anti-VEGF agents, data revealed the effect of aflibercept was prompter and more long-lasting. Areas of retinal ischemia appeared in both cases. However, they were observed faster in the case of patients treated with aflibercept. Thus, neovascular AMD is a disease that occurs with age, it can be early detected by OCT and slowed the progression to central blindness with intravitreal treatment.

Efficacy and Safety of Aflibercept Therapy for Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

Purpose: To assess the real-world efficacy and safety of aflibercept for the treatment of diabetic macular edema (DME). Methods: A systematic search was conducted across multiple databases. Articles were included if participants had DME and received aflibercept treatment for a minimum of 52 ± 4 weeks. Primary outcomes included changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). A risk of bias assessment of studies was completed, pooled estimates were obtained, and a meta-regression was performed. Information on adverse events was collected. Results: The search yielded 2112 articles, of which 30 were included. Aflibercept was more effective than laser photocoagulation functionally (12-month BCVA-weighted mean difference [WMD] = 10.77 letters, P < 0.001; 24 months = 8.12 letters, P < 0.001) and anatomically (12-month CMT WMD = -114.12 µm, P < 0.001; 24 months = -90.4 µm, P = 0.004). Compared to bevacizumab, aflibercept was noninferior at improving BCVA at 12 months (WMD = 1.71 letters, P = 0.34) and 24 months (WMD = 1.58 letters, P = 0.083). One study found that aflibercept was more effective than bevacizumab anatomically at 1 and 2 years (P < 0.001 at 12 and 24 months). Compared to ranibizumab, aflibercept rendered a greater improvement in BCVA at 1 year (WMD = 1.76 letters, P = 0.001), but not 2 years (WMD = 1.66 letters, P = 0.072). CMT was not significantly different between both therapies at 12 months (WMD = -14.30 µm, P = 0.282) and 24 months (P = 0.08). One study reported greater functional improvement with aflibercept compared with dexamethasone (P = 0.004), but inferiority in reducing CMT (P < 0.001). Meta-regression analysis demonstrated that dosing schedule was found to impact outcomes at 12 and 24 months, while study design and sample size did not impact outcomes at 12 months. There were minimal safety concerns using aflibercept therapy. Conclusions: Aflibercept is a safe and effective therapy option for DME in the clinical setting, performing superiorly to laser photocoagulation. Evidence regarding comparisons with bevacizumab, ranibizumab, and dexamethasone is mixed and limited.

Healthcare expenditure of intravitreal anti-vascular endothelial growth factor inhibitors compared with dexamethasone implant for diabetic macular oedema.

PURPOSE: The aim of this study was to estimate the 1-year costs associated with treating diabetic macular oedema (DME) patients using current intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics compared with the dexamethasone implant. METHODS: We conducted a descriptive cost-evaluation analysis using data from Oslo University Hospital and literature to compare three different intravitreal drugs for DME: bevacizumab, aflibercept and dexamethasone. Stratification of patients into 'Naive' or 'Switch' group was based on treatment history. We estimated the costs from healthcare and 'extended' healthcare perspectives. Sensitivity analysis evaluated the impact of various parameters. RESULTS: The average injections per patient per year for the Naive group (bevacizumab), Switch group (aflibercept) and dexamethasone were 9.5, 9.1 and 3.0 respectively. From a healthcare perspective, the 1-year costs for the Naive group were 15% lower (bevacizumab, €3619), and for the Switch group, 23% higher (aflibercept, €5226) compared with dexamethasone (€4252). The 'extended' healthcare perspective showed the cost per patient per year for bevacizumab remained nominally lower in the Naive group, while dexamethasone remained lower for the Switch group (€5116 for dexamethasone, compared to €4987 for bevacizumab and €6537 for aflibercept). CONCLUSIONS: From a primary healthcare perspective, the dexamethasone as a first-line DME treatment may increase economic costs in settings where bevacizumab is used off-label. Treating resistant DMEwith dexamethasone may reduce the costs and treatment burden compared with switching to aflibercept.

The effect of posterior vitreous detachment on aflibercept response in diabetic macular oedema.

PURPOSE: To investigate the effect of posterior vitreous detachment (PVD) on aflibercept response in treatment-naïve diabetic macular oedema (DME). DESIGN: A retrospective cohort study. METHODS: One hundred and fifty eyes of 150 treatment-naïve patients with DME were enrolled. The patients were divided into three groups according to their PVD status: group 1 (no PVD during injections), group 2 (PVD during injections) and group 3 (PVD already present initially). Three consecutive aflibercept injections at intervals of 1 month were applied to all patients. The efficacy of the aflibercept treatment on DME was assessed by comparing changes in central retinal thickness (CRT) and best-corrected visual acuity (BCVA) values after three loading dose injections. RESULTS: After three consecutive injections, the mean reduction of CRT in groups 1, 2 and 3 were -199.6±106.9, -224.9±124.1 and -210.7±126.3, respectively. The decrease in CRT was significant in all groups (p<0.001 in all groups, paired-samples t-test); however, mean changes in CRT were similar among groups (all p>0.05, one-way analysis of variance (ANOVA)). The mean improvement in BCVA in groups 1, 2 and 3 was 6.6±0.9, 6.5±0.8 and 6.1±0.4 ETDRS letters, respectively. The improvement of BCVA was significant in all groups (p<0.001 in all groups, paired-samples t-test) and mean changes were similar between groups (p>0.05, one-way ANOVA). There was no significant relationship between the presence or development of PVD and the mean decrease of CRT and improvement of BCVA (for CRT r=-0.052, p=0.531 and for BCVA r=-0.078, p=0.342). CONCLUSION: In the present study, it was observed that the efficacy of aflibercept treatment in patients with DME did not depend on PVD status.

Thrombotic Microangiopathy and Acute Kidney Injury Induced After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors VEGF Blockade-Related TMA After Intravitreal Use.

Vascular endothelial growth factor (VEGF) inhibition can cause worsening hypertension, proteinuria, chronic kidney injury, and glomerular disease. Thrombotic microangiopathy (TMA) and other nephrotic disorders have been reported with systemic VEGF blockade. These same agents are given intravitreally for age-related macular degeneration (AMD) and diabetic retinopathy (DR), albeit at lower doses than those given for systemic indications. Systemic absorption of anti-VEGF agents when given intravitreally has been shown consistently along with evidence of significant intravascular VEGF suppression. While worsening hypertension has only been seen in some large-scale studies, case reports show worsening proteinuria and diverse glomerular diseases. These include TMA-associated lesions like focal and segmental glomerulosclerosis with collapsing features (cFSGS). In this paper, we report three cases of TMA likely associated with the use of intravitreal anti-VEGF therapy. These patients developed the signature lesion of VEGF blockade in a 6 to 11 month time frame after starting intravitreal VEGF inhibitors. The literature is reviewed showing similar cases. Intravitreal VEGF blockade may cause these adverse events in a hitherto unidentified subgroup of patients. Well-controlled prospective observational trials are needed to determine the event rate and identify which subgroups of patients are at increased risk. A registry for patients who develop worsening hypertension, proteinuria exacerbation, and glomerular diseases from intravitreal VEGF blockade is proposed.

Macular Hole Surgery in the Case of Wet Age-Related Macular Degeneration Treated with Intravitreal Aflibercept.

A 72-year-old male treated with aflibercept (Eylea) due to choroidal neovascularization (CNV) in his left eye developed a full-thickness macular hole (MH) after the second injection. The occurrence of MH in his left eye resulted in further visual acuity deterioration. As a consequence of having developed the MH, the patient was operated on. Phacoemulsification and vitrectomy with internal limiting membrane peeling and 20% SF6 tamponade were performed. MH closure was achieved and best corrected visual acuity improved to the extent allowed by CNV. The patient continued anti-VEGF treatment with Eylea due to wet age-related macular degeneration in his left eye. The observation period of 2 years has been uneventful and visual acuity of 0.2 has remained stable.

Outcomes in patients receiving fixed-dosed aflibercept for treatment-naïve neovascular age-related macular degeneration during one year of routine clinical practice. / Aflibercept intravítreo en dosis fijas en pacientes naïve con degeneración macular asociada a la edad neovascular: resultados a un año en práctica clínica real.

OBJECTIVE: To investigate the visual and anatomical outcomes of aflibercept as therapy in patients with treatment-naïve neovascular age-related macular degeneration during one year in routine clinical practice. METHODS: The study was a retrospective, case series, including 35 patients, 38 eyes, with neovascular age-related macular degeneration that received aflibercept injections (Eylea®). Patients received a loading dose of 3monthly injections (2mg / 0.05ml) followed by intravitreal injections every 2 months. RESULTS: At 3 and 12 months, the mean best-corrected visual acuity improved significantly as compared with baseline (ETDRS 50.5±14.5 and 53.1±14.5 vs. 39.6±14.7, respectively, P<.05). At 3 and 12 months, the proportion of patients who improved visual acuity by ≥15 letters was 37.1% and 45.7%, respectively. The mean decrease in central macular thickness was also significant after loading dose (239.6±52.0µm) and at 12 month (227±53.2µm) compared with pre-treatment values (370.3±117, 6) (P<.001). Resolution of pigment epithelial detachment (PED) was also observed in 14 out of 20 (70%) eyes with PED at baseline. CONCLUSION: Aflibercept administered by fixed dosing over one year improved visual acuity and macular morphology in treatment-naïve eyes in routine daily practice.

Biosimilars in ophthalmology: "Is there a big change on the horizon?"

Retinal disease management has witnessed remarkable advances in posterior segment pharmacotherapy with the development of anti-VEGF molecules such as Lucentis® (ranibizumab), Eylea® (aflibercept), and off-label bevacizumab (Avastin). The US patents for ranibizumab and aflibercept will expire in 2020 (though Regeneron has indicated that it might attempt to extend its US patent to June 2023 with additional patent claims), and their European patents will expire in 2022 and 2025. Aflibercept comes off patent in 2022 in People's Republic of China and Japan. As soon as each patent expires, biosimilar molecules could potentially come in the mainstream clinical practice as a more cost-efficient choice in the form of generic biosimilars. It is difficult to predict how significant this shift would be in terms of more cost-effective clinical management and how it will impact the care in developed and developing world. It is important for clinicians to have a clear understanding about ophthalmic biosimilars before the industry brings these molecules to the mainstream clinical use globally.

The involvement of NK1 and Y2 receptor in the development of laser-induced CNVs in C57Bl/6N mice.

PURPOSE: to explore whether the NK1 and Y2 receptors are involved in the pathogenesis of laser-induced CNV (choroidal neovascularization) in C57Bl/6N mice. METHODS: CNV was induced by laser damage of Bruch's membrane and the CNV volume was determined by OCT and/or flatmount preparation. First, the development of the CNV volume over time was evaluated. Second, the CNV development in NK1- and Y2 KO mice was analyzed. Third, the effect on the development as well as the regression of CNV by intravitreal injections of the NK1 antagonist SR140333 and the Y2 antagonist BIIEO246 separately and each in combination with Eylea®, was investigated. Furthermore, flatmount CNV volume measurements were correlated to volumes obtained by the in vivo OCT technique. RESULTS: CNV volume peak was observed at day 4 after laser treatment. Compared to wild type mice, NK1 and Y2 KO mice showed significantly smaller CNV volumes. Eylea® and the Y2 antagonist significantly reduced the volume of the developing CNV. In contrast to Eylea® there was no effect of either antagonist on the regression of CNV, additionally no additive effect upon combined Eylea®/antagonist treatment was observed. There was a strong positive correlation between CNV volumes obtained by OCT and flatmount. CONCLUSION: NK1 and Y2 receptors mediate the development of laser-induced CNVs in mice. They seem to play an important role at the developmental stage of CNVs, whereas VEGF via VEGF receptor may be an important mediator throughout the CNV existence. In vivo OCT correlates with flatmount CNV volume, representing a useful tool for in vivo evaluations of CNV over time.

Switching between ranibizumab and aflibercept for the treatment of neovascular age-related macular degeneration.

The introduction of antivascular endothelial growth factor agents such as ranibizumab and aflibercept has revolutionized the management of neovascular age-related macular degeneration. A number of randomized clinical trials have shown that ranibizumab and aflibercept produce similar efficacy and safety outcomes. Most of the switching studies published to date show that efficacy benefits are uncontrolled, retrospective trials with limitations in terms of their selection, monitoring, numbers, and assessment criteria. Based on the published literature to date, we propose arguments for and against switching antivascular endothelial growth factor agents, provide our own perspective on this topic, and suggest a focus for future research.

Effect of Eylea on recombinant AAV2-VEGF-induced choroidal neovascularization / 中华实验眼科杂志

Objective To evaluate the effect of Eylea (aflibercept) on recombinant adeno-associated virus 2 (AAV2)-vascular endothelial growth factor (VEGF)-induced choroidal neovascularization (CNV).Methods Two normal cynomolgus monkeys were used in this study.Recombinant AAV2-VEGF was delivered by subretinal injection (60 μl/eye,7.0×1011 IU/ml) into both eyes for each cynomolgus monkey.Both eyes of one animal were treated with single intravitreal injection of Eylea (50 μl/eye,40 mg/ml) 3 weeks after AAV2-VEGF injection,and the two eyes of the other animal were untreated.Optical coherence tomography (OCT),electroretinography (ERG),fluorescein angiography (FFA) and ocular photography were conducted.The experiment was approved by the Institutional Animal Care and Use Committee (IACUC) at JOINN Laboratories (Suzhou) (IACUC serial number:ACU15-1112).Results OCT showed that subretinal hyperreflective material,retinal edema,choroid edema and local pigment epithelial detachment were found after injection of recombinant AAV2-VEGF.All of those symptoms were relieved after treated with Eylea,but aggravated after 4 weeks treated with Eylea.FFA showed that the area of fluorescein leakage expanded obviously after 2 weeks treated with AAV2-VEGF,and it was observed at the whole of fundus posterior pole at 5 weeks after injection.After 1 week treated with Eylea,the area of fluorescein leakage decreased obviously,but increased gradually after 4 weeks treated with Eylea.ERG results showed that the amplitude of ERG decreased gradually after injection of recombinant AAV2-VEGF.After intravitreal injection of Eylea,the amplitude of ERG increased gradually,but it decreased again after 4 weeks treated with Eylea.Conclusions Injection of recombinant AAV2-VEGF is capable of inducing CNV and pathological retinal in cynomolgus monkey.Eylea can prevent the development of clinically relevant CNV,but the effect just lasts for a period.

Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes.

INTRODUCTION: The review aims to discuss effects of vitrectomy on pharmacokinetics of anti-vascular endothelial growth factor (anti-VEGF) agents, and attempt to provide treatment guidance. Areas covered: An Embase search was conducted using the terms 'anti-VEGF', 'pegaptanib', 'ranibizumab', 'bevacizumab', 'aflibercept', 'pharmacokinetics', 'half-life', 'clearance', 'metabolism', 'vitrectomy', 'vitrectomized'. Published data regarding the pharmacokinetic properties of the above drugs and the effect of vitrectomy in animal and human eyes was reviewed. Expert opinion: There are limited studies on the effect of vitrectomy on pharmacokinetic properties of anti-VEGF drugs in human eyes. Most animal models indicate that intravitreal drugs have reduced half-lives and increased clearance in vitrectomized eyes. More studies, with carefully selected design, are required to explore this further. However, considering existing evidence, it is important to consider vitreous and lens status when monitoring and treating patients. Authors recommend fixed monthly dosing, with low threshold for increasing frequency of injection even to 2-weekly if required, as well as close monitoring of patients to establish individual response. There may be an increased role for slow-release steroid implants in vitrectomized eyes with DME or RVO. Longer acting substances currently under development such as brolucizumab or abicipar pegol, may become the treatment of choice in the future.