Aflibercept Does Not Suppress Angiopoietin-2 in Patients With nAMD or DME.
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ABSTRACT:
SUBMITTER: Avery RL
PROVIDER: S-EPMC10561785 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Aflibercept Does Not Suppress Angiopoietin-2 in Patients With nAMD or DME.
Avery Robert L RL Csaky Karl G KG Westenskow Peter P Stoilov Ivaylo I Diack Cheikh C
Translational vision science & technology 20231001 10
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Project description:PurposeTo analyse the effect of intravitreal aflibercept injections on systemic angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-A levels in patients with neovascular age-related macular degeneration (nAMD).MethodsIn a prospective, randomized study, aflibercept (2.0 mg/50 µl) or ranibizumab (0.5 mg/50 µl) was administered intravitreally to 38 treatment-naive patients. Blood samples were taken before, 7 days after, and 28 days after the first intravitreal therapy. Cytokine levels were measured by enzyme-linked immunosorbent assay. Twenty-two age- and sex-matched individuals served as controls.ResultsAt baseline, there were no significant differences of systemic Ang2 and VEGF-A levels among the treatment and control groups. After intravitreal aflibercept administration, median (interquartile range: IQR) systemic Ang2 was significantly upregulated from 1819 pg/ml (1262-3099) to 2123 pg/ml (1441-3769; p = 0.011) 7 days after the drug injection and remained non-significantly elevated at 1944 pg/ml (1431-2546 pg/ml; p = 0.653) 28 days after the drug injection. Median (IQR) systemic VEGF-A levels were significantly reduced from 43 pg/ml (30-57) to 8 pg/ml (8-8; p < 0.0001) 7 days and 16 pg/ml (8-26; p = 0.001) 28 days after the injection in the aflibercept group. There were no significant effects on systemic VEGF-A and Ang2 levels in the ranibizumab group at any time point following the first injection.ConclusionIn this study, we report significant systemic upregulation of Ang2 after intravitreal aflibercept administration. This counterregulatory response may represent a potential escape mechanism from antiangiogenic therapy.
| S-EPMC8519089 | biostudies-literature
Project description:BackgroundDiabetic macular edema (DME) shows a gradual and sustained functional and morphologic response to anti-vascular endothelial growth factor (VEGF) drugs, but the optimal schedule for initiation of anti-VEGF therapy is not known. This study evaluates the treatment response behavior of DME in the Phase 3 trials of intravitreal aflibercept, with 5 initial intravitreal aflibercept injections (IAI), 2 mg every 4 weeks (2q4), in the upload phase.MethodsThis post hoc pooled analysis of the VISTA-DME (NCT01363440) and VIVID-DME (NCT01331681) trials evaluated the change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) during the upload phase, using pooled data from both IAI treatment groups [2q4 and 2 mg every 8 weeks (2q8)]. The mean visit-to-visit change in BCVA and CRT, and the respective rate of gainers and losers was calculated for each successive visit. A secondary analysis compared the visit-to-visit change in BCVA between the 2q4 and 2q8 treatment arms during the upload period and the first year treatment period.ResultsThe majority of eyes showed a continuing improvement of BCVA after the first IAI. The proportions of eyes gaining BCVA (≥5 letters) at each visit compared with the previous visit during the IAI 2q4 upload phase were 60 (4-weeks), 19 (8-weeks), 16 (12-weeks), 15 (16-weeks), and 14 % (20-weeks). In contrast, the proportions of eyes losing BCVA (≥5 letters) were 3 (4-weeks), 7 (8-weeks), 7 (12-weeks), 9 (16-weeks), and 8 % (20-weeks), respectively. The odds of BCVA (≥5 letters) gain/loss exceeded 1.7 at each visit (range 1.7-20). Overall, the proportion of patients with BCVA gain ≥5 letters at week 20 (compared with baseline) was 76 and 80 % in the 2q4 and 2q8 groups, respectively. The proportions of eyes showing a visit-to-visit decrease in CRT of ≥30 µm during the first 5 IAI were 77 (4-weeks), 27 (8-weeks), 21 (12-weeks), 17 (16-weeks), and 12 % (20-weeks). In the secondary analysis, the BCVA outcomes were similar for the 2q8 and 2q4 treatment arms.ConclusionsThe data presented here are consistent with continual functional and anatomic improvement following the fourth and fifth initial 2q4 injections, suggesting that an intensive and sufficiently long upload may be beneficial. Trial registration VIVID-DME: Clinicaltrials.gov: NCT01331681; VISTA-DME: Clinicaltrials.gov: NCT01363440.
| S-EPMC5088462 | biostudies-literature
Project description:Purpose: To assess the effect of higher dose (HD) aflibercept on visual acuity (VA), optical coherence tomography outcomes, and injection burden in eyes with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) that responded suboptimally to standard-dose aflibercept. Methods: This retrospective analysis included eyes with clinically significant disease activity on monthly therapy (AMT) (injection interval ≤35 days) or clinically significant increased activity on extension (IAE) (injection interval >36 days) that were switched from aflibercept 2 mg to aflibercept HD (3 mg to 4 mg). Outcomes were assessed at baseline, after injections 1 through 4, and at 6, 9, and 12 months. Results: Overall, 318 eyes of 288 adult patients were analyzed (eyes with nAMD: 59 AMT, 147 IAE; eyes with DME: 50 AMT, 62 IAE). Most of the study cohort received aflibercept HD 3 mg (nAMD: 73% AMT and 58% IAE; DME: 49% AMT and 68% IAE); the remainder received 4 mg. The mean best VA improved significantly with AMT and was maintained with IAE. In all groups, the central subfield thickness decreased significantly and the mean injection intervals increased or remained stable. No new safety signals were observed. Conclusions: Aflibercept HD might improve outcomes while decreasing treatment burden for eyes that respond suboptimally to standard dosing.
| S-EPMC10037750 | biostudies-literature
Project description:PurposeAnti-vascular endothelial growth factor (anti-VEGF) therapies, which attenuate the capacity of VEGF to bind to VEGF receptors, are standard-of-care options for various retinal disorders that are characterized by pathologic retinal angiogenesis and vascular permeability. Multiple receptors and ligands have also been reported as being involved in these pathways, including angiopoietin-1 (ANG1) and angiopoietin-2 (ANG2).MethodsElectrochemiluminescence immunoassays were used to detect human VEGF (hVEGF), as well as rabbit ANG2 and basic fibroblast growth factor protein levels in vitreous samples derived from a study evaluating the efficacy of the anti-VEGF agents ranibizumab, aflibercept, and brolucizumab in an hVEGF165-induced rabbit retinal vascular hyperpermeability model.ResultshVEGF was completely suppressed in rabbit vitreous after anti-VEGF treatment for 28 days. ANG2 protein in vitreous and ANGPT2 mRNA in retina tissue were similarly suppressed, although the anti-VEGF agents do not directly bind to ANG2. Aflibercept demonstrated the greatest inhibitory effect in ANG2 levels in vitreous, which correlated with strong, durable suppression of intraocular hVEGF levels.ConclusionsThis study explored the effects of anti-VEGF therapies beyond direct binding of VEGF by evaluating protein levels and the expression of target genes involved in angiogenesis and associated molecular mechanisms in the rabbit retina and choroid.Translational relevanceIn vivo data suggest that anti-VEGF agents currently used for the treatment of retinal diseases could provide beneficial effects beyond direct binding of VEGF, including suppression of ANG2 protein and ANGPT2 mRNA.
| S-EPMC10198290 | biostudies-literature
Project description:Several standard-of-care therapies for the treatment of retinal disease, including aflibercept, inhibit vascular endothelial growth factor (VEGFA). The main shortcoming of these therapies is potential undertreatment due to a lack of compliance resulting from the need for repeated injections. Gene therapy may provide sustained levels of anti-VEGFA proteins in the retina following a single injection. In this nonhuman primate study, we explored whether ADVM-022, a recombinant adeno-associated virus (AAV) vector designed to express aflibercept, could induce anti-VEGFA protein levels comparable with those observed following a single-bolus intravitreal (IVT) injection of the standard-of-care aflibercept recombinant protein. The results demonstrated that intraocular levels of aflibercept measured at 56 days after a single IVT injection of ADVM-022 were equivalent to those in the aflibercept recombinant protein-injected animals measured 21-32 days post-administration. ADVM-022-injected animals exhibited signs of an initial self-limiting inflammatory response, but overall all doses were well tolerated. ADVM-022 administration did not result in systemic exposure to aflibercept at any dose evaluated. These results demonstrated that a single IVT injection of ADVM-022 resulted in safe and efficacious aflibercept levels in the therapeutic range, suggesting the potential of a gene therapy approach for long-term treatment of retinal disease with anti-VEGF therapy.
| S-EPMC7341454 | biostudies-literature
Project description:PurposeTo compare intravitreal nesvacumab (anti-angiopoietin-2) + aflibercept vs intravitreal aflibercept injection (IAI) in neovascular age-related macular degeneration (nAMD).MethodsEyes were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, week 4, and week 8. The LD combo was continued every 8 weeks (q8w). At week 12, the HD combo was re-randomized to q8w or every 12 weeks (q12w) and IAI was re-randomized to q8w, q12w, or HD combo q8w through week 32.ResultsThe study comprised 365 eyes. At week 12, the mean best-corrected visual acuity (BCVA) gains from baseline were similar in the LD combo group, HD combo group, and IAI group (5.2 letters, 5.6 letters, and 5.4 letters, respectively); the mean central subfield thickness (CST) reductions were similar (182.2 µm, 200.0 µm, and 178.6 µm, respectively). The mean changes in BCVA and CST through week 36 were similar across groups. At week 12, complete retinal fluid resolution was observed in 49.1% (LD combo), 50.8% (HD combo), and 43.6% (IAI) of eyes; the proportions with a CST of 300 μm or less were similar across groups. Numerical trends at week 32 toward complete retinal fluid resolution with combination treatment were not maintained at week 36. Serious ocular adverse events were infrequent and comparable across groups.ConclusionsIn nAMD, nesvacumab + aflibercept showed no additional BCVA or CST benefit over IAI monotherapy.
| S-EPMC9954160 | biostudies-literature
Project description:PurposeTo report the impact of baseline central retinal thickness (CRT) on outcomes in patients with diabetic macular edema (DME) in VIVID-DME and VISTA-DME.MethodsPost hoc analyses of two randomized controlled trials in which 862 DME patients were randomized 1 : 1 : 1 to treatment with intravitreal aflibercept 2.0 mg every 4 weeks (2q4), intravitreal aflibercept 2.0 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation at baseline and as needed. We compared visual and anatomical outcomes in subgroups of patients with baseline CRT < 400 μm and ≥400 μm.ResultsAt weeks 52 and 100, outcomes with intravitreal aflibercept 2q4 and 2q8 were superior to those in laser control-treated patients regardless of baseline CRT. When looked at in a binary fashion, the treatment effect of intravitreal aflibercept versus laser was not significantly better in the ≥400 μm than the <400 μm group; when looked at as a continuous variable, baseline CRT seemed to have an impact on the treatment effect of intravitreal aflibercept versus laser.ConclusionsPost hoc analyses of VIVID-DME and VISTA-DME demonstrated the benefits of intravitreal aflibercept treatment in DME patients with baseline CRT < 400 μm and ≥400 μm. This trial is registered with NCT01331681 and NCT01363440.
| S-EPMC5896224 | biostudies-literature
Project description:NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
| S-EPMC2486339 | biostudies-other
Project description:Treat and extend (T&E) is a standard treatment regimen for treating neovascular age-related macular degeneration (nAMD) with anti-vascular endothelial growth factors (anti-VEGFs), but the treatment intervals attained are not well documented. This retrospective, non-comparative, non-randomised study of eyes with nAMD classified treatment interval sequences in a T&E cohort in Australia using Electronic Medical Records (EMR) data. We analysed data from 632 treatment-naïve eyes from 555 patients injected with ranibizumab, aflibercept or unlicensed bevacizumab between January 2012 and June 2016 (mean baseline age 78.0). Eyes were categorised into non-overlapping clusters of interval sequences based on the first 12 months of follow-up. We identified 523 different treatment interval sequences. The largest cluster of 197 (31.5%) eyes attained an 8-week treatment interval before dropping to a shorter frequency, followed by 168 (26.8%) eyes that did not reach or attained a single 8-week interval at the end of the study period. A total of 65 (10.4%) and 83 (13.3%) eyes reached and sustained (≥2 consecutive injection intervals of the same length) an 8 and 12 weekly interval, respectively. This study demonstrates highly individualised treatment patterns in the first year of anti-VEGF therapy in Australia using T&E regimens, with the majority of patients requiring more frequent injections than once every 8 weeks.
| S-EPMC6802800 | biostudies-literature
Project description:BACKGROUND/AIMS:To evaluate intravitreal aflibercept versus laser in subgroups of patients with baseline Diabetic Retinopathy Severity Scale (DRSS) scores ≤43, 47, and ≥53 in VIVID-DME and VISTA-DME. METHODS:Patients with diabetic macular oedema were randomised to receive intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation at baseline with sham injections at every visit. These post hoc analyses evaluate outcomes based on baseline DRSS scores in patients in the integrated dataset. The 2q4 and 2q8 treatment groups were also pooled. RESULTS:748 patients had a baseline DRSS score based on fundus photographs (≤43, n=301; 47, n=153; ≥53, n=294). At week 100, the least squares mean difference between treatment groups (effect of intravitreal aflibercept above that of laser, adjusting for baseline best-corrected visual acuity) was 8.9 (95% CI 5.99 to 11.81), 9.7 (95% CI 5.54 to 13.91), and 11.0 (95% CI 7.96 to 14.1) letters in those with baseline DRSS scores ≤43, 47, and ≥53, respectively. The proportions of patients with ≥2 step DRSS score improvement were greater in the intravitreal aflibercept group versus laser, respectively, for those with baseline DRSS scores of ≤43 (13% vs 5.9%), 47 (25.8% vs 4.5%), and ≥53 (64.5% vs 28.4%). CONCLUSIONS:Regardless of baseline DRSS score, functional outcomes were superior in intravitreal aflibercept-treated patients, demonstrating consistent treatment benefit across various baseline levels of retinopathy. TRIAL REGISTRATION NUMBERS:NCT01331681 and NCT01363440, Post-results.
| S-EPMC6047149 | biostudies-literature