Macular Degeneration
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High-dose Aflibercept with Increased Dosing Intervals as a New Standard of Care for DMO and nAMD

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Published Online: May 11th 2023 touchREVIEWS in Ophthalmology. 2023;17(1):8–9 DOI:
Authors: Sean Adrean
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The introduction of vascular endothelial growth factor inhibitors has led to significant improvements for patients with neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO). Landmark trials – such as ANCHOR, MARINA and VIEW for nAMD and RIDE/RISE, VIVID and VISTA for DMO – showed positive results, including clinically meaningful gains in Early Treatment Diabetic Retinopathy Study letters, with anti-vascular endothelial growth factor agents now the standard of care for nAMD and DMO. More recent studies, including those investigating high-dose aflibercept in nAMD and DMO, have focused on durability of response by studying increased treatment intervals to reduce the treatment burden on patients and physicians alike. The PULSAR (nAMD) and PHOTON (DMO) trials included high-dose (8 mg) aflibercept at either 12-week or 16-week dosing intervals and showed non-inferior visual gains compared with the standard dose of 2 mg, with ≥83% of patients maintaining their extended dosing interval throughout the 48-week studies. This is certainly an exciting development, and it will be interesting to see how extended treatment durability will impact management paradigms for patients with nAMD and DMO.


Aflibercept, diabetic macular oedema, macular oedema, neovascular age-related macular degeneration, randomized clinical trials, vascular endothelial growth factor


With the introduction of monoclonal antibody inhibitors for all isoforms of vascular endothelial growth factor (VEGF)-A, which were first presented in September 2005 with off-label use of bevacizumab, significant anatomical and visual improvements for neovascular age-related macular degeneration (nAMD) became a reality. Following the landmark ANCHOR and MARINA trials, which showed that monthly ranibizumab injections resulted in 7.211.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained after 1 year of treatment, anti-VEGF agents became the standard of care for nAMD.1,2 The VIEW trials for nAMD studied aflibercept, a recombinant protein that fuses portions of VEGF receptors 1 and 2 to the Fc portion of human immunoglobulin G1, creating a trap for the VEGF molecules.3 In the trial, which increased the time interval between treatments to 8 weeks after a loading phase, 8.49.3 ETDRS letters were gained at 1 year. This further cemented the value of anti-VEGF therapy.3

Although reported results for nAMD were excellent, the adoption of anti-VEGF agents for diabetic macular oedema (DMO) was much slower. This was probably due to the slow anatomical and visual improvements noted after singular anti-VEGF injections. It took the very positive results of the RIDE/RISE trials of ranibizumab, which showed an increased vision of 8.59.9 ETDRS letters after 2 years, for the treatment landscape of DMO to start changing.4 Then, the VIVID and VISTA trials of aflibercept in DMO showed that between 9.4 and 11.0 ETDRS letters were gained, even with increased dosing intervals.5 With the results of these clinical trials, anti-VEGF therapy became the definitive standard of care for DMO.5 The Diabetic Retinopathy Clinical Research Network group compared aflibercept, ranibizumab and bevacizumab for the treatment of DMO in Protocol T.6 The 1year results revealed that, in participants whose initial vision was 20/50the aflibercept treatment arm gained 18.9 ETDRS letters at 1 yeara statistically significant increase compared with bevacizumab and ranibizumab arms, which gained 11.8 and 14.2 letters, respectively.6 Aflibercept has continued to play an increasingly prominent role in the treatment of DMO.

Although the initial responses in patients with nAMD were positive, the visual acuity improvements waned over time; this was at least in part due to the different treatment strategies employed by retina specialists. The three main treatment strategies included the pro re nata (PRN) modality, fixed interval dosing (the mainstay of clinical trials) and the treatandextend approach. The treatandextend method was widely adopted by the retina community to maximize treatment outcomes while reducing treatment burden. Some practices adopted the treatextendstop protocol, whereby therapy cessation was reached after two 12week time intervals of non-activity were observed.7

With the PRN approach, many patients were found to be undertreated. This was elucidated in SEVEN UP, the extension trial of the first clinical trials ANCHOR, MARINA and HORIZONand in CATT 5, the extension trial of CATT, which mainly use PRN treatment strategies once the trials were complete. Those studies found worse visual outcomes over time. The SEVEN-UP trial, which included 7-year outcomes in patients treated with ranibizumab in the ANCHOR, MARINA and HORIZON trials, showed a total loss of 8.6 ETDRS letters from baseline, and a total of 19 letters were lost using the best corrected visual acuity score at the end of the clinical trials.8 Similar results were found in the CATT trial when the 5year results were published.9 The mean change in vision was a loss of 3 letters from baseline and an overall loss of 11 letters in best corrected visual acuity at the end of the trial.9

While the PRN results showed worse vision over time, Peden et al. found much better visual outcomes with fixedinterval dosing, with 12.1 ETDRS letters gained at 7 years.10 Adrean et al. found results comparable to clinical trials, such as VIEW 1 and 2, ANCHOR and MARINA, with an 8.7 letter gain at the 8year timepoint using the treatextendstop approach.7 While both of these approaches led to excellent visual outcomes over the long term, multiple treatments were required to maintain these visual outcomes, with an average of 10.5 injections per year in the fixedinterval dosing study and 8.1 injections per year in the treat–extend–stop study.7,10

Notably, the Adrean et al. study switched many patients to aflibercept from other anti-VEGF agents.7 When examining the results of long-term switchers to aflibercept, Adrean et al. found that it required an average of 7.7 injections in the first year and 6.5 injections per year by year 3Although an 8.1 ETDRS letter gain was observed after an average of 5.7 years of therapy, with aflibercept being used for the last 3 years of treatment, patients still required injections every 8 weeks on average.11 While this was an improvement from an injection every 56 weeks, further decreases in treatment burden were desired by patients and retina surgeons alike.11

The YOSEMITE and RHINE trials in DMO,12 and the TENAYA and LUCERNE trials in nAMD13 investigated the use of faricimab, a bispecific antibody targeting VEGF and angiopoietin 2 (ang-2). The ang-2 pathway is upregulated in some pathological conditions, resulting in increased vascular permeability; by inhibiting this pathway, vessel stability is promoted. In one of the arms of the YOSEMITE and RHINE studies (one-third of the patients) durability of treatment was examined.12 Findings showed that 7174% of patients with DMO could be maintained with 1216week treatment intervals at the 1year timepoint.12 These trials demonstrated non-inferior anatomical and visual outcomes compared with aflibercept dosed every 8 weeks. In the combined faricimab arms, there was a 10.711.6 ETDRS letter gain compared with 10.310.9 letter gain with aflibercept for patients with DMO.12 In the TENAYA and LUCERNE nAMD trials, the average visual gain at 1 year was 5.86.6 compared with 5.16.6 ETDRS letters for aflibercept, which also demonstrated non-inferiority.13 In the nAMD trials after the loading phase, between 78% and 80% of patients on faricimab were maintained on the 1216week dosing intervals.13

The PULSAR and PHOTON studies demonstrated increasing durability by quadrupling the concentration of aflibercept from 2.0 mg to 8.0 mg in 0.07 mL injections in order to achieve two more half lives.14,15 Impressively, in the high-dose (HD) group of the PHOTON trial studying DMO91% of patients in the 12week dosing group and 89% of patients in the 16week group maintained their dosing intervals throughout the 48week study.14 Combined, 93% of the HD arms were on a 12week treatment interval throughout the study. Visual gains in the HD 8.0 mggroup were found to be non-inferior to the gains in the 2.0 mgdosing group at 1 year.14

PULSAR enrolled treatmentnaïve patients with nAMD.15 Overall, 83% of the aflibercept HD treatment arm remained on dosing interval of 12 weeks or longer throughout the first year of the study, with 79% of the 12week arm and 77% of the 16week arm remaining on their treatment regimen.15 Visual gains in the aflibercept HD group were found to be non-inferior to those in the 2.0 mg group receiving 8week dosing.15 Additionally, a greater proportion of the 8.0 mg aflibercept group was fluid free compared with the 2.0 mg group at 16 weeks; this key secondary endpoint was statistically significant.15

Since the durability of treatment response was successfully demonstrated by extended dosing intervals with aflibercept, it will certainly be exciting to add this new treatment to our armamentarium of options for nAMD and DMOIt will also be fascinating to see how treatment paradigms will change. Will retina specialists continue to use a treatandextend approach, or will fixedinterval dosing once again become the preferred treatment strategy? With the potential for only requiring three or four treatments per year, will retina specialists even attempt to stop therapy, and if so, after how many years of injections will they consider therapy cessation in nAMD and DMO?

Article Information:

Sean Adrean has received grant support from Genentech and Regeneron.

Compliance With Ethics

This article is an opinion piece and does not report on new clinical data or any studies with human or animal subjects performed by the author.

Review Process

Double- blind peer review.


The named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval for the version to be published.


Sean Adrean, Retina Consultants of Orange County, 301 W. Bastanchury Rd. #285 Fullerton, CA 92861, USA. E:


No funding was received in the publication of this article.


This article is freely accessible at © Touch Medical Media 2023

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this article.




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2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–31. DOI: 10.1056/NEJMoa054481

3. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537–48. DOI: 10.1016/j.ophtha.2012.09.006

4. Quyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789–801.

5. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122:2044–52. DOI: 10.1016/j.ophtha.2015.06.017

6. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203. DOI: 10.1056/NEJMoa1414264

7. Adrean SD, Chaili S, Ramkumar H, et al. Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti–VEGF injections using a treat-extend-stop protocol. Ophthalmology. 2018;125:1047–53. DOI: 10.1016/j.ophtha.2018.01.012

8. Rofagha S, Bhisitkul RB, Boyer DS, et al. SEVEN-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120:2292–9. DOI: 10.1016/j.ophtha.2013.03.046

9. Maguire MG, Martin DF, Ying G-S, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: The comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123:1751–61. DOI: 10.1016/j.ophtha.2016.03.045

10. Peden MC, Suñer IJ, Hammer ME, Grizzard WS. Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration. Ophthalmology. 2015;122:803–8. DOI: 10.1016/j.ophtha.2014.11.018

11. Adrean SD, Knight D, Chaili S, et al. Long term results of patients with neovascular age-related macular degeneration switched from other anti-VEGF agents to intravitreal aflibercept. Int J Retina Vitreous. 2022;8:11. DOI: 10.1186/s40942-022-00361-9

12. Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): Two randomised, double-masked, phase 3 trials. Lancet. 2022;399:741–55. DOI: 10.1016/S0140-6736(22)00018-6

13. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): Two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399:729–40. DOI: 10.1016/S0140-6736(22)00010-1

14. Brown DM, on behalf of the PHOTON study investigators. Intravitreal aflibercept injection 8 Mg for DME: 48-week results from the phase II/III photon trial. Presented at: American Academy of Ophthalmology Annual Meeting 2022, Chicago, IL, 30 September–3 October 2022.

15. Lanzetta P, on behalf of the PULSAR study investigators. Intravitreal aflibercept injection 8 Mg for namd: 48-week results from the phase III PULSAR trial. Presented at: American Academy of Ophthalmology Annual Meeting 2022, Chicago, IL, 30 September–3 October 2022.

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