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Treat-And-Extend Therapy Using Aflibercept for Neovascular Age

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Treat-And-Extend Therapy Using Aflibercept for Neovascular Age Treat-and-Extend Therapy Using Aflibercept for Neovascular Age-related Macular Degeneration: A Prospective Clinical Trial FRANCIS CHAR DECROOS, DAVID REED, MURTAZA K. ADAM, DAVID SALZ, OMESH P. GUPTA, ALLEN C. HO, AND CARL D. REGILLO PURPOSE: To determine the efficacy and durability of HOROIDAL NEOVASCULARIZATION (CNV) CAUSES aflibercept used in a treat-and-extend (TAE) regimen the vast majority of severe visual loss from for neovascular age-related macular degeneration neovascular age-related macular degeneration C 1 (NVAMD). (NVAMD). Intravitreal vascular endothelial growth fac- DESIGN: Multicenter, prospective, open label, noncom- tor (VEGF) blockade has revolutionized the treatment of parative, interventional study. NVAMD. Ranibizumab (Lucentis; Genentech, Inc) and METHODS: Forty eyes of 40 patients with treatment- bevacizumab (Avastin; Genentech, Inc) are anti-VEGF naı¨ve NVAMD were managed with a TAE regimen of agents that have been extensively studied.2–7 intravitreal aflibercept. The main endpoints were the Ranibizumab is currently approved by the U.S. Food and change in mean and median best-corrected visual acuity Drug Administration for treatment of NVAMD, while from baseline at years 1 and 2. Other endpoints included bevacizumab is used in an off-label fashion. mean number of annual injections and treatment More recently, the fully human, soluble recombinant intervals. VEGF receptor decoy aflibercept (Eylea; Regeneron Phar- RESULTS: Thirty-five (87.5%) and 31 patients maceuticals, Inc) was approved for treatment of NVAMD. (77.5%) completed year 1 and year 2, respectively. Aflibercept is a recombinant fusion protein consisting of The mean letter gain was 7.2 (P < .001) and 2.4 the extracellular domain of the human VEGF receptors 1 (P [ .269) letters at 1 and 2 years, respectively, (Ig2 domain) and 2 (Ig3 domain) fused to the Fc domain from a mean baseline of 58.9 letters (20/63 Snellen of human IgG1. The clinical efficacy of aflibercept for treat- equivalent). The median visual gain was 11.5 and 7.5 ment of CNV was established in trials evaluating afliber- letters at 1 and 2 years, respectively, from a median cept, namely the VEGF-Trap Eye: Investigation of baseline of 59.0 letters (20/63 Snellen equivalent). Efficacy and Safety in Wet AMD parts 1 and 2 (VIEW The mean number of injections was 8.0 and 6.5 during 1/2) studies, with reported results demonstrating that afli- the first and second year, respectively. Twelve-week or bercept administration was noninferior to ranibizumab longer treatment intervals were used in 35% and 38% dosed every 4 weeks. The VIEW 1/2 studies included a of patients during the first- and second-year time points, treatment arm that initially evaluated aflibercept injec- respectively. tions once every 8 weeks after 3 successive loading doses 8 CONCLUSION: Intravitreal aflibercept TAE therapy led given every 4 weeks. to significant visual improvement in eyes with NVAMD Although the pivotal trials demonstrated that serial at 1 year, with some loss in the visual gains at the end anti-VEGF treatments were effective for NVAMD, of year 2 that was not related to loss of exudative control. monthly follow-up was required except in the aforemen- TAE therapy with aflibercept is a rational strategy to tioned treatment arm within the VIEW 1/2 studies. reduce treatments and clinic evaluations over 2 years Mandated monthly follow-up can be cumbersome for pa- with satisfactory outcomes. (Am J Ophthalmol tients, caregivers, and treating physicians alike, and the 2017;180:142–150. Ó 2017 Elsevier Inc. All rights challenges presented by maintaining monthly follow-up reserved.) intervals generated interest in alternative intravitreal in- jection dosing strategies. One such strategy is the treat- and-extend (TAE) approach, initially described in 2007 by Spaide.9 TAE is a dosing paradigm in which the affected Supplemental Material available at AJO.com. eye is injected at each patient visit with a variable follow- Accepted for publication Jun 7, 2017. up interval that is tailored to individual treatment From the Retina Service, Wills Eye Hospital/Mid Atlantic Retina, 10 Philadelphia, Pennslyvania (F.C.D., D.R., M.K.A., D.S., O.P.G., response. The TAE regimen uses optical coherence to- A.C.H., C.D.R.); and Southeastern Retina Associates, Chattanooga, mography (OCT) based on detection of macular fluid to Tennessee (F.C.D.). direct management. Several retrospective11–16 and Inquiries to Carl D. Regillo, Director, Retina Service, Wills Eye 17–21 Hospital/Mid Atlantic Retina, 840 Walnut St, Suite 1020, Philadelphia, prospective series demonstrated that TAE using PA 19107; e-mail: [email protected] bevacizumab and/or ranibizumab for NVAMD reduced 142 © 2017 ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2017.06.002 the number of both follow-up visits and treatments intervals owing to the follow-up interval variability neces- compared with monthly dosing, while still achieving sitated by a treat-and-extend management paradigm. Best- satisfactory anatomic and functional outcomes.11,14 TAE corrected ETDRS visual acuity and CFT measured by employing aflibercept has not been prospectively spectral-domain OCT were reported at 7 prespecified characterized in a clinical trial, though retrospective time points: baseline, 1 month, 3 months, 6 months, series have examined aflibercept TAE in eyes previously 12 months, 18 months, and 24 months. treated with other anti-VEGF agents22,23 or in 15 combination therapy with other anti-VEGF agents. TREATMENT ADMINISTRATION: Study eyes fulfilling The TAE dosing regimen may be particularly suitable in inclusion criteria received an intravitreal 2 mg aflibercept conjunction with intravitreal administration of aflibercept, treatment at the initial visit and at each subsequent study as pharmacokinetic modeling of this treatment demon- visit. No specified loading doses were mandated. If all strated prolonged VEGF binding activity compared with extension criteria were not met 4 weeks after the baseline bevacizumab or ranibizumab.24 Prolonged binding may visit, the patient underwent repeat evaluation and treat- potentially correlate to fewer injections required for long- ment after 4 weeks. Until all extension criteria were term control of exudation in NVAMD. Before performing met, patients were subsequently followed and treated at a comparative study against bevacizumab or ranibizumab 4-week intervals. Extension criteria included absence of TAE, it is important to first prospectively investigate the macular fluid on OCT, defined as any intraretinal, subreti- efficacy and durability of aflibercept TAE monotherapy. nal, or sub–retinal pigment epithelial fluid; absence of The Aflibercept Treat and extend for Less frequent Admin- vision loss of 5 or more letters from the prior visit; absence istration Study (ATLAS) is the first multicenter, prospec- of new macular hemorrhage; and absence of increased tive study to help characterize the efficacy and durability lesion size or leakage on FA. Of note, FA was not of the TAE dosing regimen with intravitreal aflibercept mandated at any visit after the initial evaluation, but for NVAMD. could be performed at any visit at the discretion of the investigator. When a patient met extension criteria, the previous follow-up/treatment interval was increased by 2-week in- METHODS tervals to a maximum interval of 16 weeks. If a patient was being treated at an interval between 6 and 16 weeks, STUDY DESIGN: This prospective, open-label, multi- but failed to meet extension criteria at a particular visit, center, investigator-sponsored clinical study enrolled 40 treatment was administered and the follow-up interval patients. Prospective Institutional Review Board (IRB) was then reduced by 2-week increments until all extension approval was obtained (#20122054), all experimental pro- criteria were met once again. After NVAMD disease was cedures adhered to the tenets of the Declaration of deemed to be inactive based on fulfillment of all extension Helsinki, and all participants engaged in an informed con- criteria, the follow-up interval was then increased to a sent process and signed a written consent document prior maximum final interval of 2 weeks less than the subject’s to enrollment in the ATLAS (ClinicalTrials.gov Identifier: prior maximum treatment interval where disease reactiva- NCT01773954). The criteria for study inclusion included tion was noted. This limit was specified to minimize the patients of age greater than 55 years with treatment-naı¨ve, number of exudative recurrences. active, subfoveal NVAMD demonstrating macular fluid on spectral-domain OCT and CNV leakage on fluorescein OUTCOME MEASURES: The major endpoints of this angiography (FA). Only 1 eye for each patient demon- 2-year study were mean and median change from baseline strating a pretreatment best-corrected visual acuity in BCVA at years 1 and 2. Secondary outcomes included (BCVA) of 20/25 to 20/320 was eligible. Exclusion criteria change from baseline in CFT, the percentage of patients for the study included prior treatment for NVAMD, any with 20/40 or better Snellen equivalent vision, percentage concurrent progressive retinal disease, or prior vitrectomy of patients gaining or losing 15 or more letters of vision, in the study eye. Patients previously treated with systemic mean treatment interval, mean number of injections and anti-VEGF therapy, photodynamic therapy, or thermal distribution of treatment intervals at the first- and laser were also excluded. At each visit, patients
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