October 2014, Issue 74

Treat and Extend Management of Neovascular AMD: What Data Do We Have?

Charles C. Wykoff, MD, PhD Retina Consultants of Houston Clinical Assistant Professor of Ophthalmology, Weill Cornell Medical College, Houston Methodist Hospital Houston, Texas

Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss with approximately 200,000 new cases diagnosed each year in the United States.¹ Pharmaceutical agents including ranibizumab, aflibercept and bevacizumab, which block vascular endothelial growth factor-A (VEGF), have revolutionized the management of AMD, and disease stability along with visual improvement can be achieved in many patients with treatment.^2-5 The key trials illustrating these benefits have employed three management strategies: monthly treatment, monthly visits with pro re nata (PRN) retreatment upon evidence of exudative disease activity, or monthly treatment for 3 months and then treatment every other month.

The major trials comparing monthly with PRN dosing, including CATT, HARBOR and IVAN, have consistently demonstrated better visual outcomes with monthly dosing.^4,6,7 Despite these confirmed better outcomes with fixed monthly treatment, PRN management does achieve substantial clinical benefit with a reduced treatment frequency of approximately four fewer treatments in the first year (approximately 6-7 versus 10-11 injections).

PRN trials including PrONTO, CATT and HARBOR have revealed considerable variability in the number of injections administered: some patients receive monthly treatment indefinitely while a majority of patients can be managed with substantially fewer treatments.⁸ This variability indicates that treatment tailored to a given patient’s clinical response may be optimal. Underscoring this concept, intraocular levels of VEGF can vary among patients with phenotypically similar diseases over a range of diagnoses.⁹ Importantly, persistent or recurrent exudative disease activity (as illustrated by intraretinal fluid) is a marker for worse visual outcomes compared to a dry, exudation-free macula.¹⁰

A treat and extend (TREX) protocol employs monthly injections until signs of exudation have resolved.¹¹ Then, the interval between visits is lengthened sequentially, typically by 1 to 2 weeks, as long as there are no signs of recurrent exudation. Treatment is rendered at every visit and the time between visits is individualized based on each patient’s response. When recurrent disease is detected, the treatment interval is reduced. The goal is to maintain an exudation-free macula while minimizing the treatment burden with fewer office visits, tests and injections. TREX protocols can reduce the burden of care and cost of care delivery substantially, and are utilized by over 77% of retina specialists in the United States.¹²

Many retrospective studies have supported a TREX approach. For example, Gupta et al reported an analysis of 92 eyes.¹³ During a mean follow-up of 1.5 years, a wide range of treatment frequencies was observed, with only 7 eyes (8%) receiving monthly dosing throughout the study period due to persistent exudation.

Multiple prospective protocols have demonstrated clinical efficacy of a TREX approach in treatment-naïve eyes with neovascular AMD, although none of the reported studies has directly compared monthly to TREX dosing. Toalster et al¹⁴ reported 1-year outcomes of a single-arm, non-randomized study in which 45 patients treated with ranibizumab gained a mean of 7 Snellen letters and 47% of patients did not demonstrate recurrent exudation following 3 initial monthly doses, allowing extension to the maximum treatment interval with delivery of the minimum number of treatments (7).

Abedi et al published 2-year outcomes of a single-arm prospective study involving 120 patients treated with ranibizumab and/or bevacizumab according to a TREX protocol with a maximum extension interval of 12 weeks; 84% of patients completed year 2 with a mean gain of 9.5 and 8.0 ETDRS best-corrected visual acuity (BCVA) letters at 12 and 24 months, respectively.¹⁵ These gains were similar to those observed with monthly treatment in the ranibizumab phase 3 trials but with substantially fewer injections: a mean of 8.6 and 5.6 injections in the first and second years, respectively, for a mean total of 14.2 treatments over 2 years compared to approximately 22 injections with monthly dosing.¹⁶

LUCAS is the largest prospective TREX trial to date in which over 400 patients in Norway were randomized to ranibizumab or bevacizumab with a maximum extension interval of 12 weeks.¹⁷ At 1 year, the ranibizumab and bevacizumab cohorts performed equally well visually, gaining a mean of 8.5 and 8.3 ETDRS BCVA letters, respectively, with the ranibizumab cohort receiving significantly fewer retreatments (8.0 vs 8.8, P=0.002).¹⁸

Other prospective TREX protocols are underway.^19,20 An ongoing controlled TREX protocol is the TREX AMD multicenter trial which includes 60 patients randomized to intravitreal ranibizumab 0.5mg either monthly or TREX with a 2-year primary
endpoint.²⁰

A TREX approach to neovascular AMD offers the opportunity to individualize management while minimizing treatment burden. It is the most common strategy employed clinically in the United States, and is supported by both retrospective and prospective data with more data forthcoming.

References

1. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch of Ophthalmol. 2004;122(4):564-572.
2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Eng J Med. 2006;355(14):1432-1444.
3. Heier JS, Brown DM, Chong V, et al. Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration. Ophthalmology. 2012;119(12):2537-2548.
4. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Eng J Med. 2011;364(20):1897-1908.
5. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Eng J Med. 2006;355(14):1419-1431.
6. Busbee BG, Ho AC, Brown DM, et al. Twelve-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-related Macular Degeneration. Ophthalmology. 2013;120(5):1046-1056.
7. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267.
8. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148(1):43-58 e41.
9. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Eng J Med. 1994;331(22):1480-1487.
10. Brown DM, Tuomi L, Shapiro H. Anatomical measures as predictors of visual outcomes in ranibizumab-treated eyes with neovascular age-related macular degeneration. Retina. 2013;33(1):23-34.
11. Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007;143(4):679-680.
12. PAT Survey 2014. ASRS. http://www.asrs.org/content/documents/_2013asrspatsurveyresults.pdf .
13. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010;117(11):2134-2140.
14. Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extend regimen for ranibizumab treatment of age-related macular degeneration. Retina. 2013;33(7):1351-1358.
15. Abedi F, Wickremasinghe S, Islam AF, et al. Anti-VEGF treatment in neovascular age-related macular degeneration: a treat-and-extend protocol over 2 years. Retina. 2014. 2014 Aug;34(8):1531-8.
16. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65 e55.
17. LUCAS (Lucentis Compared to Avastin Study) Phse IV Trial http://clinicaltrials.gov/ct2/results?term=LUCAS&Search=Search .
18. Lucentis Compared to Avastin Study (LUCAS). American Academy of Ophthalmology. 2013. New Orleans, LA, USA.
19. Repeated Eye Injections of Aflibercept for Treatment of Wet Age Related Macular Degeneration (ATLAS) Phase 4 Trial. http://clinicaltrials.gov/ct2/show/NCT01773954?term=Regillo&rank=1 .
20. Treat and Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab (T-REX)/ Phase IIIb Multicenter Trial. http://clinicaltrials.gov/ct2/show/NCT01748292?term=wykoff&rank=2 .