Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration

doi:10.1016/j.ophtha.2012.09.006

Ophthalmology

Volume 119, Issue 12, December 2012, Pages 2537-2548

Presented at: the American Academy of Ophthalmology Annual Meeting, October 22–25, 2011, Orlando, Florida. This is an Annual poster presentation.

, , , , , , , , , , , , , , , , , , ,

https://doi.org/10.1016/j.ophtha.2012.09.006 Get rights and content

Objective

Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab.

Design

Double-masked, multicenter, parallel-group, active-controlled, randomized trials.

Participants

Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.

Intervention

Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).

Main Outcome Measures

The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures.

Results

All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.

Conclusions

Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Design

The “VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD” studies (VIEW 1 and VIEW 2) were similarly designed, prospective, double-masked, multinational, parallel-group, active-controlled, randomized clinical trials. The investigators from the VIEW 1 and VIEW 2 studies are listed in Appendix 1, available at http://aaojournal.org. Patients in VIEW 1 (registered at www.clinicaltrials.gov on July 31, 2007; NCT00509795. Accessed August 8, 2012) were randomized at 154 sites in the United

Patient Disposition, Baseline Characteristics, and Exposure

The disposition of patients is shown in Figure 1A-B. In VIEW 1, 1217 patients were randomized, with 91.1% to 96.4% of patients completing 52 weeks. In VIEW 2, 1240 patients were randomized, with 88.1% to 91.1% completing 52 weeks. Baseline demographics and disease characteristics were evenly balanced among all treatment groups (Table 1). The mean number of active injections received by patients in all monthly treatment arms, which were scheduled to receive 13 monthly injections, was 12.1 to

Discussion

We have described 2 large and similarly designed clinical trials involving more than 2400 patients with neovascular AMD. In both trials, all 3 aflibercept treatment regimens (including the every-2-month regimen after 3 initial monthly loading doses) were statistically noninferior to monthly ranibizumab in preventing moderate visual acuity loss at 1 year, meeting the primary outcome of the trials; all the aflibercept regimens also met the stricter margin of 5% for clinical equivalence compared

Acknowledgments

The authors thank Karen Chu, MS, Regeneron Pharmaceuticals, Inc, and Avner Ingerman, MD, initial study director of VIEW 1 and former employee of Regeneron Pharmaceuticals, Inc, for assistance with the design of the studies. Editorial and administrative assistance to the authors who wrote the manuscript was provided by S. Balachandra Dass, PhD, Regeneron Pharmaceuticals, Inc.

References (20)

G.D. Yancopoulos
Clinical application of therapies targeting VEGF
Cell
(2010)
U. Schmidt-Erfurth et al.
Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study
Ophthalmology
(2011)
D.S. Boyer et al.
A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration
Ophthalmology
(2009)
M.A. Singer et al.
HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration
Ophthalmology
(2012)
D.F. Martin et al.
Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results
Ophthalmology
(2012)
U. Chakravarthy et al.
Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial
Ophthalmology
(2012)
J.S. Heier et al.
The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor Trap-Eye dosed as-needed after 12-week fixed dosing
Ophthalmology
(2011)
D.M. Brown et al.
Primary endpoint results of a phase II study of vascular endothelial growth factor Trap-Eye in wet age-related macular degeneration
Ophthalmology
(2011)
N.G. Congdon et al.
Important causes of visual impairment in the world today
JAMA
(2003)
Laser photocoagulation of subfoveal neovascular lesions in age-related macular degenerationResults of a randomized clinical trial
Arch Ophthalmol
(1991)

There are more references available in the full text version of this article.

Cited by (1890)

Systemic Arterial and Venous Thrombotic Events Associated With Anti–Vascular Endothelial Growth Factor Injections: A Meta-Analysis
2024, American Journal of Ophthalmology
To compare the risk of systemic arteriovenous thrombotic events between intravitreal anti–vascular endothelial growth factor (anti-VEGF) and sham injections.
Random-effects meta-analysis.
A systematic search was performed on OVID MEDLINE, Embase, and Cochrane Library from January 2005 to August 2023. Our inclusion criteria were randomized controlled trials (RCTs) reporting on systemic arteriovenous events for standard dose intravitreal anti-VEGF agents for any indication.
A total of 20 RCTs reporting on 12,833 eyes were included. There was no significant difference in the risk of any thrombotic event between bevacizumab 1.25 mg and ranibizumab 0.5 mg (Risk ratio (RR) = 0.96, 95% CI = 0.52-1.75, P = .89). There was no significant difference between bevacizumab and ranibizumab when restricting to arterial thrombotic events (RR= 0.88, 95% CI = 0.60-1.30, P = .53) or venous thrombotic events (RR = 1.99, 95% CI =86 0.68-5.82], P = .21). The risk of arterial thrombotic events was similar between aflibercept and bevacizumab (RR = 1.11, 95% CI = 0.60-2.07, P = .74), between aflibercept and ranibizumab (RR= 0.77, 95% CI = 0.49-1.21, P = .26), between brolucizumab and aflibercept (RR= 0.67, 95% CI = 0.32-1.38, P = .27), and between aflibercept and faricimab (RR = 0.96, 95% CI = 0.43-2.17, P = .93). Compared to sham, neither dose of ranibizumab (0.5 mg or 0.3 mg) showed a higher risk of arterial thrombotic events.
There was a similar risk of systemic arteriovenous thrombotic adverse events between anti-VEGF agents and between ranibizumab and sham injections.
VEGF Inhibition Associates With Decreased Risk of Mortality in Patients With Neovascular Age-related Macular Degeneration
2024, Ophthalmology Science
Controversy exists regarding the systemic safety of intravitreal VEGF inhibitors in the treatment of neovascular age-related macular degeneration (nAMD). We aimed to investigate the potential impact of VEGF inhibitor treatment on the risk of all-cause mortality and cardiovascular disease (CVD) among patients with nAMD.
A nationwide register-based cohort study with 16 years follow-up.
Patients with nAMD exposed with VEGF inhibitors (n = 37 733) and unexposed individuals without nAMD (n = 1 897 073) aged ≥ 65 years residing in Denmark between January 1, 2007, and December 31, 2022.
Cox proportional hazards analysis was conducted to assess the effect of intravitreal VEGF inhibitor treatment on all-cause mortality and incident CVD.
In a predefined analysis plan we defined primary outcomes as hazard ratios (HRs) of all-cause mortality and a composite CVD endpoint in patients with nAMD treated with VEGF inhibitors compared with individuals without nAMD. The secondary outcomes encompassed analyses that explored the impact of the number of doses and the association between exposure and outcome over a specific time period.
Overall, 63.7% of patients with nAMD were women with an average age of 69.9 years (interquartile range 65.0–76.0 years). Patients exposed to VEGF inhibitors demonstrated a reduced risk of all-cause mortality compared with individuals without nAMD (HR, 0.79; 95% confidence interval [CI], 0.78–0.81), and an increased risk of composite CVD (HR, 1.04; 95% CI, 1.01–1.07). The decreased risk of all-cause mortality persisted, but there was no significant association between VEGF inhibitor treatment and CVD when patients with nAMD were grouped by the number of doses or considered exposed within 60 days postinjection.
Our study revealed a decreased risk of all-cause mortality and a 4% increased risk of CVD among patients with nAMD exposed with VEGF inhibitors. The decreased risk of mortality is unlikely to be directly pathophysiologically related to VEGF inhibitor treatment. Instead, we speculate that patients undergoing VEGF inhibitor treatment are, on average, individuals in good health with adequate personal resources. Therefore, they also have a higher likelihood of overall survival. These findings strongly support the safety of VEGF inhibitor treatment in terms of all-cause mortality and CVD among patients with nAMD.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Influence of serial intravitreal injections on measures of dry eye: A systemic review and meta-analysis
2024, Contact Lens and Anterior Eye
The aim of this study was to evaluate the long-term effects of serial intravitreal injections (IVI) on measures of dry eye.
The PubMed, EMBASE, and Cochrane databases were searched according to the PROSPERO protocol (CRD42023455727). Studies evaluating the influence of serial IVI on the ocular surface compared with untreated fellow eyes were included. The measures of dry eye after IVI were used as outcome variables. The results are presented as mean difference (MD) with a corresponding 95% confidence interval (CI).
A total of 4 studies with 259 participants were included in this meta-analysis. Significant increases in ocular surface disease index (OSDI) scores (MD 10.26, 95 % CI 5.05 to 15.46, p ＜ 0.01) and tear film osmolarity (TOsm; MD 4.40, 95 % CI 0.87 to 7.92, p = 0.01) were observed in the IVI treated eyes compared to the untreated fellow eyes. There was no significant difference between the groups with respect to fluorescein tear film break-up time (TBUT; p = 0.05), average non-invasive tear film break-up time (NITBUT; p = 0.94), first NITBUT (p = 0.78) and Schirmer test (p = 0.94).
Repeated IVI of anti-VEGF agents with preoperative povidone-iodine application was associated with increased OSDI scores and TOsm, while no significant difference was found in fluorescein TBUT, average NITBUT, first NITBUT and Schirmer test. The ocular surface may partially recover after the procedures, but IVI still has deleterious effects on the ocular surface.
Clinically compliant cryopreservation of differentiated retinal pigment epithelial cells
2024, Cytotherapy
Age-related macular degeneration (AMD) is the most common cause of blindness in elderly patients within developed countries, affecting more than 190 million worldwide. In AMD, the retinal pigment epithelial (RPE) cell layer progressively degenerates, resulting in subsequent loss of photoreceptors and ultimately vision. There is currently no cure for AMD, but therapeutic strategies targeting the complement system are being developed to slow the progression of the disease.
Replacement therapy with pluripotent stem cell-derived (hPSC) RPEs is an alternative treatment strategy. A cell therapy product must be produced in accordance with Good Manufacturing Practices at a sufficient scale to facilitate extensive pre-clinical and clinical testing. Cryopreservation of the final cell product is therefore highly beneficial, as the manufacturing, pre-clinical and clinical testing can be separated in time and location.
We found that mature hPSC-RPE cells do not survive conventional cryopreservation techniques. However, replating the cells 2–5 days before cryopreservation facilitates freezing. The replated and cryopreserved hPSC-RPE cells maintained their identity, purity and functionality as characteristic RPEs, shown by cobblestone morphology, pigmentation, transcriptional profile, RPE markers, transepithelial resistance and pigment epithelium–derived factor secretion. Finally, we showed that the optimal replating time window can be tracked noninvasively by following the change in cobblestone morphology.
The possibility of cryopreserving the hPSC-RPE product has been instrumental in our efforts in manufacturing and performing pre-clinical testing with the aim for clinical translation.
Maintenance of Vision Needed to Drive after Intravitreal Anti-VEGF Therapy in Patients with Neovascular Age-related Macular Degeneration and Diabetic Macular Edema
2024, Ophthalmology Retina
To evaluate the association between intravitreal anti–VEGF therapy and visual acuity (VA)/driving vision maintenance over 4 years in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME).
Retrospective, observational, clinical practice cohort study using data from the Vestrum Health database.
Initial diagnosis (January 1, 2014 to June 30, 2019) of nAMD or DME and ≥ 1 year of treatment/follow-up history. The VA analysis required 4 years of treatment/follow-up history. For the driving vision maintenance analysis, patients required Snellen VA of 20/40 or better at baseline and for ≥ 6 months during year 1 after index intravitreal anti-VEGF treatment in the better-seeing eye.
A loss-of-driving event was the first clinic visit with VA worse than 20/40 sustained for ≥ 6 consecutive months. Kaplan–Meier analyses estimated the probability of maintaining driving vision over 4 years stratified by year-1 injection number. Cox proportional hazard models examined associations between baseline clinical characteristics and year-1 injection frequency and the risk of losing driving vision.
Mean change in VA over time and by baseline VA, driving vision maintenance probability over time and stratified by anti-VEGF injection frequency, and baseline factors predictive of driving vision maintenance.
In year 1, the nAMD and DME cohorts gained 8.5 and 9.5 ETDRS letters, respectively. Between years 1 and 4, patients with nAMD and DME lost 6.6 and 2.7 ETDRS letters, respectively. The probability of maintaining driving vision over 4 years was 56% (nAMD) and 72% (DME); among patients who received 1 to 5, 6 to 7, and ≥ 8 anti-VEGF injections in year 1, corresponding probabilities were 50%, 56%, and 65% (nAMD; P < 0.001) and 63%, 72%, and 77% (DME; P < 0.001). Baseline factors associated with driving vision loss included older age, worse index VA, geographic atrophy (nAMD), and worsening baseline diabetic retinopathy (DME).
Older age and worse index VA were risk factors for driving vision loss, whereas a greater year-1 injection number was associated with driving vision maintenance through year 4, supporting early initiation and frequent anti-VEGF injections for maintaining driving vision in nAMD or DME.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Increasing concentrations of intravitreal therapies for neovascular age-related macular degeneration
2024, The Lancet

View all citing articles on Scopus

: Manuscript no. 2012-1120.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): J.S.H. is a consultant to and has received research funding from Alimera, Allergan, Fovea, Genentech, Genzyme, GlaxoSmithKline, Neovista, and Regeneron Pharmaceuticals. He has also received travel support from Regeneron Pharmaceuticals. D.M.B. is a consultant to Alimera, Allergan, Bayer, Genentech/Roche, Novartis, Regeneron Pharmaceuticals, and Thrombogenics and has received research funding from Alcon, Alimera, Allergan, Eli Lilly, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, and Thrombogenics. He has also received travel support from Regeneron Pharmaceuticals and lecture fees from Genentech. V.C. is a consultant to Alimera and Bayer and has received research funding from Alcon, Allergan, Bayer, Novartis, and Pfizer. He is an advisory board member for Allergan and Novartis and has also received travel support from Bayer. J.-F.K. is a consultant to Alcon, Bayer, and Thea and an advisory board member for Allergan, Bayer, and Novartis. He has received travel support from Regeneron Pharmaceuticals. P.K.K. is a consultant to Bayer, Genentech, Novartis, and Regeneron Pharmaceuticals. He has received research funding from Regeneron Pharmaceuticals. Q.D.N. is a consultant to Bausch & Lomb and Santen and has received research funding from Genentech, Novartis, and Pfizer. B.K. has received travel support from Bayer. A.H. is a consultant to Alcon, Allergan, Centocor, Johnson & Johnson, Neovista, Merck, Ophthotech, Oraya, Paloma, P.R.N., Q.L.T., Regeneron Pharmaceuticals, and Thrombogenics. He has received research funding and lecture fees from Alcon, Allergan, Genentech, Neovista, Ophthotech, Oraya, P.R.N., Q.L.T., Regeneron Pharmaceuticals, and Second Sight. Y.O. is a consultant to Alcon and Bayer and has received travel support from Bayer. G.D.Y., N.S., R.V., A.J.B., and Y.S. are employees of Regeneron Pharmaceuticals. MA, G.G., B.S., and R.S. are employees of Bayer HealthCare. C.S.'s institution has received payments from the Medical University of Vienna for data monitoring/reviewing and statistical analysis. U.S.-E. is a consultant to Alcon, Allergan, Bayer HealthCare, and Novartis, and an advisory board member for Alcon and Novartis. She has received travel support from Bayer HealthCare and lecture fees from Bayer HealthCare and Novartis.

: G.D.Y. and N.S., incorporating the advice of a panel of academic and physician experts, developed the initial proposal for the VIEW 1 study design. The study design of both studies was further developed and finalized by the academic authors and clinical and statistical authors from Regeneron Pharmaceuticals and Bayer HealthCare (sponsors). The sponsors conducted the trials and together with the investigators gathered the data. Study conduct and analyses were supervised by the Study Steering Committees and the sponsors. The Writing Committee consisting of authors J.S.H., D.M.B., V.C., and U.S.-E. (subteam of VIEW Steering Committees) along with G.D.Y. composed the first draft of the paper, which was critically revised and finalized by the input of all coauthors. The Writing Committee members and all other authors met authorship criteria. All coauthors had full and unrestricted access to the data and decided to publish the paper vouching for the accuracy and completeness of the reported data.

: Funding: Sponsored by Regeneron Pharmaceuticals, Inc, Tarrytown, New York, and Bayer HealthCare, Berlin Germany. The sponsors participated in the design and conduct of the study, analysis of the data, and preparation of the manuscript.

^⁎: Group members listed online in Appendix 1 (http://aaojournal.org).

View full text

Original articleIntravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration

Objective

Design

Participants

Intervention

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Study Design

Patient Disposition, Baseline Characteristics, and Exposure

Discussion

Acknowledgments

Cell

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Important causes of visual impairment in the world today

JAMA

Laser photocoagulation of subfoveal neovascular lesions in age-related macular degenerationResults of a randomized clinical trial

Arch Ophthalmol

Original article
Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration