scholarly journals Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration

2020 ◽  
Author(s):  
Ramin Tadayoni ◽  
Laura Sararols ◽  
Georges Weissgerber ◽  
Rohini Verma ◽  
Andreas Clemens ◽  
...  
Keyword(s):  
Disease Control ◽  
Macular Degeneration ◽  
Antibody Fragment ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Pivotal Phase ◽  
Anti Vegf ◽  
Age Related

Background Despite the success of anti-vascular endothelial growth factors (anti-VEGF), there is currently a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). Purpose To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment designed specifically for intraocular use in humans. Methods In this article, we summarize the pre-clinical and current clinical evidence for brolucizumab, with an outlook to other treatment regimens and additional indications under investigation. Results The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dosing in one intra-vitreal injection compared with other anti-VEGF agents. The Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal Phase III trials HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. Conclusions The pre-clinical and clinical data for brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.

scholarly journals Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration

Ophthalmology ◽  
2016 ◽  
Vol 123 (5) ◽  
pp. 1080-1089 ◽  
Author(s):  
Frank G. Holz ◽  
Pravin U. Dugel ◽  
Georges Weissgerber ◽  
Robin Hamilton ◽  
Rufino Silva ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Antibody Fragment ◽  
Age Related Macular Degeneration ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Vegf Inhibitor ◽  
Age Related ◽  
Single Chain Antibody Fragment

A Randomized, Double-Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Patients with Visual Impairment due to Diabetic Macular Edema (KITE)

2020 ◽  
Vol 237 (04) ◽  
pp. 450-453
Author(s):  
Justus G. Garweg
Keyword(s):  
Randomized Clinical Trials ◽  
Vision Loss ◽  
Antibody Fragment ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Single Chain ◽  
Anti Vegf ◽  
Age Related ◽  
Severity Scores ◽  
Large Phase

Abstract Background Brolucizumab is a single-chain variable antibody fragment (scVF) that specifically binds to VEGF-A. The results of two large phase III, multicentre, randomized clinical trials comparing intravitreal treatment with Brolucizumab and Aflibercept in neovascular age-related degeneration demonstrated its potency in the treatment of neovascular age-related macular degeneration (nAMD). Methods The currently tested injected dose of 6 mg Brolucizumab results in a 11.2 – 13.3 times higher equivalent molar dose compared to Aflibercept 2 mg. Thus, it is conceivable that the effect of Brolucizumab in DME exceeds that of other currently used anti-VEGF agents with regards to effect durability; this was confirmed for nAMD in a phase I/II study. Results Approved anti-VEGF drugs have shown unprecedented success compared to laser treatment with regards to restoration of visual acuity and improvement of diabetic retinopathy severity scores for up to 5 years. The visual gains were sustained after the loading phase and a reduced number of injections were required after the first year independent of the treatment strategy. Compared to pan-retinal laser photocoagulation, the time to progression of DRP was markedly extended and was proven by better preservation of the visual field, prevention of severe vision loss, hemorrhagic complications, and the need for intraocular surgery. Conclusions The ongoing prospective, randomized, phase III clinical studies in DME, KITE, and KESTREL aim to confirm the non-inferiority of Brolucizumab 6 mg compared to Aflibercept 2 mg on a functional and morphological level as well as durability effect over 2 years.

scholarly journals Ranibizumab in Treatment for Age-related Macular Degeneration

2013 ◽  
Vol 07 (02) ◽  
pp. 109
Author(s):  
Javier Araiz ◽  
Luis Arias ◽  
Alfredo García-Layana ◽  
José María Ruiz-Moreno ◽  
◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Significant Proportion ◽  
Antibody Fragment ◽  
Age Related Macular Degeneration ◽  
Long Term Results ◽  
Office Visits ◽  
Intravitreal Ranibizumab ◽  
Anti Vegf ◽  
Age Related ◽  
Number Of Injections

Ranibizumab is an antibody fragment (Fab) that binds and inhibits all isoforms of vascular endothelial growth factor (VEGF), which is considered the main target in neovascular age-related macular degeneration (nAMD). Based on scientific evidence of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR)/Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) studies, intravitreal ranibizumab is indicated in all typical types of nAMD. Nevertheless, specific forms such as retinal angiomatous proliferation (RAP), polypoidal choroidal vasculopathy (PCV) and bad or non-responders may need combination therapies to increase the efficacy and reduce the number of injections. Due to the frequent office visits and injections required with a monthly ranibizumab therapy, several dosing strategies have been evaluated to maintain optimal efficacy while reducing the number of injections and visits in the clinical practice.Pro re nata(PRN) and ‘Treat and Extend’ are the most popular individualised therapeutic regimens. Few studies address long-term results of ranibizumab. It remains controversial whether initial good results can be maintained over time. AMD is a chronic disease and a significant proportion of patients require continued treatment.

scholarly journals Antivascular Endothelial Growth Factor Agents for Neovascular Age-Related Macular Degeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Ilias Zampros ◽  
Anna Praidou ◽  
Periklis Brazitikos ◽  
Panagiotis Ekonomidis ◽  
Sofia Androudi
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Macular Degeneration ◽  
Antibody Fragment ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Neovascular Amd ◽  
Anti Vegf ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is the leading cause of severe visual loss and blindness over the age of 50 in developed countries. Vascular endothelial growth factor (VEGF) is considered as a critical molecule in the pathogenesis of choroidal neovascularization (CNV), which characterizes the neovascular AMD. Anti-VEGF agents are considered the most promising way of effectively inhibition of the neovascular AMD process. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Two anti-VEGF agents have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD. Pegaptanib sodium, which is an aptamer and ranibizumab, which is a monoclonal antibody fragment. Another humanized monoclonal antibody is currently off-label used, bevacizumab. This paper aims to discuss in details the effectiveness, the efficacy and safety of these three anti-VEGF agents. New anti-VEGF compounds which are recently investigated for their clinical usage (VEGF-trap, small interfering RNA) are also discussed for their promising outcomes.

scholarly journals Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration

2019 ◽  
Vol 4 (1) ◽  
pp. e000273
Author(s):  
Irina Balikova ◽  
Laurence Postelmans ◽  
Brigitte Pasteels ◽  
Pascale Coquelet ◽  
Janet Catherine ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Treatment Response ◽  
Multiple Testing ◽  
Age Related Macular Degeneration ◽  
Patient Specific ◽  
Multiple Testing Correction ◽  
Anti Vegf ◽  
Age Related ◽  
Vegf Pathway

ObjectiveAge-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.Methods and analysisA retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.ResultsAssociation with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.ConclusionIdentifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

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