Reducing the Burden of Anti-VEGF Injections for Wet AMD
A review of current initiatives that have shown encouraging results.
Michael Engelbert, MD, PhD
The advent of anti-VEGF therapies has immeasurably improved quality of life for not only a huge number of patients but also their treating physicians, who no longer have to look on helplessly as vision deteriorates more or less rapidly. But while monthly injections of intravitreal anti-VEGF therapy for neovascular age-related macular degeneration yield visual outcomes superior to prior treatment strategies,1,2 frequent office visits and injections pose a significant burden on the healthcare system, patients and their caregivers.
Furthermore, frequent injections carry the risk of endophthalmitis, retinal detachment and sustained IOP elevations, a phenomenon that was recently reported to correlate with the number of injections.3 Attempts at reducing the number of injections, however, have had inferior visual results, as was shown in the randomized, double-blind, sham-controlled PIER trial,4 in which patients were treated quarterly following an initial series of three monthly injections.
This article will cover current efforts that show promise in reducing the injection burden.
“INDIVIDUALIZED” MAINTENANCE REGIMENS: PRONTO AND “TREAT AND EXTEND”
Attempts have been made to “individualize” the dosing regimen, to account for patients who may only need injections every two to three months, as well as for those who need more frequent injections. Two strategies have emerged and have all but replaced obligatory monthly dosing.
The first strategy to be reported on was PrONTO, or “Treat and Observe,” as it has also been called.5,6 This “individualized” strategy was tested in an open-label, nonrandomized study. Treatment was initiated with three monthly injections but dosed on an as-needed basis, depending on changes in visual acuity, clinical findings and optical coherence tomography evaluation, which were assessed monthly. While visual results similar to monthly dosing with fewer injections could be achieved, thus reducing the discomfort and risk to patients and the cost to society, patients still needed monthly visits, examinations, and OCTs with this strategy. That is still a significant burden for patients and their caregivers, as well as society, because of the associated cost of frequent office visits and imaging.
Figure 1. The multifactorial causes of neovascularization: (a) VEGF; (b) VEGF bound to VEGF receptor; (c) formation of neovasculature; (d) extravasation of inflammatory cells.
The second “individualized” maintenance regimen to be reported on was “Treat and Extend,” which was first proposed by K. Bailey Freund, MD.7 This regimen also mandates three initial monthly injections, but once stable visual acuity, an absence of macular hemorrhage and a dry OCT have been achieved, patients continue to receive regular maintenance injections at intervals increasing by two weeks, unless there is evidence of renewed disease activity, in which the interval for the next scheduled injection and examination is shortened.
Most practitioners who use this regimen do not extend the maximum interval beyond nine to 12 weeks because of the possibility of new hemorrhages during extended periods without VEGF inhibition.8-14 We were able to reduce the number of injections in two small cohorts of eyes with newly diagnosed type 1 (occult)11 and type 3 (retinal angiomatous proliferation)12 neovascularization. Eyes with type 3 vessels had a sustained visual improvement of approximately two Snellen lines, while the eyes with type 1 vessels achieved visual stabilization. The number of office visits and injections was reduced by 25% to 50% compared to a monthly dosing regimen. Similarly encouraging results have been obtained in two other recent series,13,14 and the savings resulting from this approach may be 50%, on average, according to one estimation.14
One concern with less-than-monthly injections is the occurrence of new, sight-threatening submacular hemorrhages. This concern was seen in the PIER trial, in which patients were switched from a monthly to a quarterly dosing regimen, and a significant increase in macular hemorrhages was seen.4
Our group has seen this phenomenon occur almost immediately after a “dry” high-quality OCT examination.8-10 Eyes maintained on a PrONTO-style regimen may go long intervals without VEGF suppression, and theoretically they are at a greater risk for submacular hemorrhages compared to eyes receiving more frequent preemptive anti-VEGF treatments, such as those managed with “Treat and Extend.”
A recent series from France compared an OCT-guided regimen with “Treat and Extend.”13 In this trial and in our two retrospective series, no sight-threatening macular hemorrhages occurred with “Treat and Extend.” Furthermore, mean visual results of the OCT-guided regimen in the French study were inferior, possibly because of many patients having difficulty coming to the office on a monthly basis and, therefore, missing recurrent disease activity.13
Most recently, the results of the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) have become available.15 Monthly dosing with ranibizumab or bevacizumab and PRN dosing without the usual mandated three initial injections of either drug were compared. Visual acuity results after 12 months were comparable in the groups receiving monthly injections of bevacizumab and monthly or PRN treatment with ranibizumab and were similar to the results previously published from the ANCHOR and MARINA trials.1,2
The same was true for the comparison of the two PRN regimens with either ranibizumab or bevacizumab, but the comparison between monthly and PRN bevacizumab was inconclusive, although the differences were small. This trial provides level 1 evidence for the effectiveness and safety of less-than-monthly dosing, provided close follow-up can be obtained.
Anti-VEGF Agents and PDT
Aside from refining dosing strategies for existing drugs, combination therapies using currently available anti-VEGF agents with photodynamic therapy may allow extension of treatment intervals. While two small, unmasked, uncontrolled series reported promising results,16,17 another study did not achieve a lower number of injections.18 The SUMMIT series of controlled combination therapy trials is currently under way to investigate this therapy in a rigorous fashion, and the results are expected this year.
Anti-VEGF Agents and Radiation
The theoretical advantages of radiation treatment are the anti-inflammatory and antifibrotic effects of potentially extended duration. Concerns with this treatment are bystander damage to the lens and radiation retinopathy. Combining VEGF inhibition and radiation may be able to enhance and extend the effect of either in a synergistic fashion. Two approaches are currently being pursued in clinical trials.
The CABERNET study is a phase 3 clinical trial that compares epimacular brachytherapy in combination with ranibizumab to ranibizumab monotherapy. Described briefly, a vitrectomy is performed and a delivery device armed with strontium 90 (Epi-Rad90, NeoVista) is centered over the macula by the surgeon for a defined period of time, delivering a focused dose of beta radiation and thus minimizing the theoretical potential for radiation damage to neighboring tissue.
Preliminary results have been promising in terms of visual results, and the reduction in the number of injections and in complications from radiation appear to be minimal. However, this procedure carries the usual risks of vitrectomy surgery, including potentially blinding ones, such as retinal detachment and endophthalmitis. Conclusive results from the randomized trial will hopefully become available later this year.
Another radiation-oriented approach is the office-based IRay radiosurgical system (Oraya), in which patients are exposed to X-rays through an external beam that is stereotactically focused on the macula. Phase 3 studies will test this technology's promise as a novel combination therapy in the near future.
Extended VEGF-Inhibition with VEGF Trap-Eye
VEGF Trap-Eye (Regeneron) is a fusion protein of parts of the extracellular binding domain of VEGF receptors 1 and 2, linked to the Fc region of human IgG and effectively serving as a decoy for soluble VEGF.19 Its affinity to VEGF-A may be several orders of magnitude higher than ranibizumab or bevacizumab, and it has been estimated that it will maintain efficacy in the eye for 10 to 12 weeks after injections.20
Two recent, large phase 3 trials, VIEW1 and 2, used three initial monthly injections of VEGF Trap, followed by two-month dosing, and this regimen showed vision gains similar to monthly ranibizumab.21 VEGF Trap-Eye should become available in the second half of this year. While it is not clear how retinal specialists will adapt to this new therapeutic option or how it will fare in individualized maintenance regimens, it seems very likely that this drug will further reduce the need for frequent injections.
While no cure is available for wet AMD as of yet, big improvements have been made in reducing the burden of intravitreal therapy with currently available agents, and potentially longer-lasting monotherapies and combination treatments are on the horizon for this chronic disease. RP
1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
2. Brown DM, Kaiser PM, Michels M, et al. Ranibizumab versus verteporforin for neovascular age-related macular degeneration. N Engel J Med. 2006;355:1432-1444.
3. Hoang QV, Della Torre KE, Jung JJ, Tsuang AJ, Freund KB. Multivariate analysis of clinical predictors of sustained intraocular pressure elevation due to intravitreal antivascular endothelial growth factor therapy. Under revision.
4. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145:239-248.
5. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.
6. 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;148:43-58.e1. Epub 2009 Apr 18.
7. Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007;143:679-680.
8. Barbazetto I, Saroj N, Freund KB. Dosing regimen and the frequency of macular hemorrhages in neovascular age-related macular degeneration treated with ranibizumab. Paper presented at: Annual meeting of the Retina Society; Scottsdale, AZ; September 25-28, 2008.
9. Margolis R, Freund KB. Hemorrhagic recurrence of neovascular age-related macular degeneration not predicted by spectral domain optical coherence tomography. Retinal Cases and Brief Reports, 2010;4:1-4.
10. Levine JP, Marcus I, Sorenson JA, Spaide RF, Cooney MJ, Freund KB. Macular hemorrhage in neovascular age-related macular degeneration after stabilization with antiangiogenic therapy. Retina. 2009;29:1074-1079.
11. Engelbert M, Zweifel SA, Freund KB. Long-term Follow-up for Type 1 (sub-RPE) Neovascularization using a “Treat and Extend” Dosing Regimen of Intravitreal Antivascular Endothelial Growth Factor Therapy”. Retina. 2010;30:1368-1375. Erratum in: Retina. 2011;31:208.
12. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina. 2009;29:1424-1431.
13. Oubraham H, Cohen SY, Samimi S, et al. Inject and extend dosing versus dosing as needed. A comparative retrospective study of Ranibizumab in exudative age-related macular degeneration. Retina. 2011;31:26-30.
14. 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;117:2134-2140.
15. The CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration. N Engl J Med. 2011 Apr 28. [Epub ahead of print].
16. Costaglio S, Romano MR, Rinaldi M, et al. Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Br J Ophthalmol. 2010;94:180-184.
17. Potter MJ, Claudio CC, Szabo SM. A randomized trial of bevacizumab and reduced light dose photodynamic therapy in age-related macular degeneration: the VIA study. Br J Ophthalmol. 2010;94:174-179.
18. Lim JY, Lee SY, Kim JG, et al. Intravitreal bevacizumab alone versus in combination with photodynamic therapy for the treatment of neovascular maculopathy in patents aged 50 years or older: 1-year results of a prospective clinical study. Acta Ophthalmol. 2010 March 16 [Epub ahead of print].
19. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99:11393-11398.
20. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF-Trap. Br J Ophthalmol. 2008;92:667-668.
21. Bayer and Regeneron report positive top-line results of two phase 3 studies with VEGF Trap-Eye in wet age-related macular degeneration. Regeneron Web site. http://newsromm.regeneron.com/releasedetail.cfm?ReleaseID=532099. Accessed May 24, 2011.
|Michael Engelbert, MD, PhD, practices with Vitreous-Retina-Macula Consultants of New York. He reports no financial interest in any products mentioned here. Dr. Engelbert can be reached via e-mail at firstname.lastname@example.org.|