Triple Therapy in Exudative AMD

Mark S. Hughes, MD, FACS and Delia N. Sang, MD, FACS
Ophthalmic Consultants of Boston
Schepens Eye Research Institute
Harvard Medical School, Boston, MA

Increasingly successful treatments for exudative age-related macular degeneration (AMD), involving anti-VEGF agents, place an increasing burden on patients, physicians, and the health-care delivery system in the United States and elsewhere. With the average age of AMD diagnosis at 75 years,¹ our currently approved treatments for choroidal neovascularization (CNV) in AMD labeled for administration monthly or every 6 weeks^2,3 may result in newly diagnosed patients theoretically facing a decade or more of nine to 12 yearly visits for monitoring and treatments of their disease.

Reduced dosing schedules for vascular endothelial growth factor (VEGF) inhibitors have shown promise for reducing the treatment burden while maintaining efficacy,⁴ but these strategies have not yet been evaluated in prospective randomized clinical trials.

A number of combination therapies have been evaluated in small case series. The goal of these combination treatments is to take advantage of possible synergies among the complementary modes of action of different agents to provide similar efficacy to already approved therapies while reducing the frequency of treatment required.

This paper reviews the rationale for combination therapy and presents results of a prospective case series in which we evaluated the effectiveness of one particular combination of therapies — reduced duration photodynamic therapy (PDT) plus intravitreal injection of dexamethasone and ranibizumab (Lucentis, Genentech, South San Francisco, California) — in treatment-naive patients with CNV due to AMD.

Rationale: Safety

One primary underlying rationale for combination therapy is to reduce risk. Reducing the frequency of dosing of vascular endothelial growth factor (VEGF) inhibitors hypothetically lessens systemic risk. Chronic use of nonselective VEGF-blockade theoretically may increase the risk of thromboembolic events^5,6 and bleeding events and may affect neuroprotection, with possible implications for stroke recovery,⁷ Alzheimer disease,⁸ and Parkinson disease.⁹

An interim data analysis in the SAILOR (Safety assessment of intravitreal Lucentis for AMD) clinical trial showed a higher incidence of stroke with the higher dose of ranibizumab (1.2% in the group treated with 0.5 mg ranibizumab vs. 0.3% in the group treated with 0.3 mg).¹⁰ This information was announced by Genentech in a letter to health care providers in January 2007, when average follow-up time in the trial was 230 days. The 1-year data from the trial have not yet been published.

In addition to the theoretical systemic risk, there are also intraocular risks with the use of VEGF inhibitors. Potential risks of anti-VEGF monotherapy include damage to the retinal pigment epithelium (RPE) and choriocapillaris with exacerbation of RPE geographic atrophy, and risk of neuronal damage with progressive retinal thinning. There are also direct risks associated with intravitreal injection, including infection and retinal detachment, and these are multiplied with schedules that call for multiple injections.

Rationale: Efficacy

The pathophysiology of CNV in AMD is multifactorial, and anti-VEGF monotherapy does not address all aspects of the condition. VEGF inhibition targets angiogenesis, but CNV also includes an inflammatory component and a vascular component — i.e., larger vessels with established structural elements that are not affected by VEGF inhibition.

Combinations of different modes of treatment for CNV may help to address the inflammatory and vascular components of the disease. For instance, intravitreal corticosteroids, which are angiostatic and help to reinforce the blood-retinal barrier,^11,12 may quiet the inflammatory component of CNV. PDT may be used to occlude the more mature blood vessels not susceptible to anti-VEGF agents.^13,14 On the other hand, PDT also up-regulates the production of VEGF and other inflammatory mediators,¹⁵ but steroids may help to limit the VEGF up-regulation and other inflammatory activity.^16-17 These characteristics may offer complementary or synergistic effects when used in combination to treat CNV.

Also, it must be remembered that not all patients respond to anti-VEGF monotherapy. Up to 20% of patients respond slowly to ranibizumab, and up to 10% of patients in the two major prospective clinical trials of the drug lost visual acuity,^5,6 so this must be considered in our treatment approach.

Combination Therapy Trials

To take advantage of potential synergies, a number of investigators have evaluated combinations of two or more of these treatment modalities. Published reports of combinations used to treat CNV in AMD have included anti-VEGF agents plus PDT,^18,19 steroids plus PDT,^20,21 and all three modalities together.^22-24

Ongoing trials of combination therapies include VERITAS (Verteporfin Intravitreal Triamcinolone Acetonide Study), combining PDT and a corticosteroid; LEVEL (Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD), evaluating induction with ranibizumab or bevacizumab and maintenance with pegaptanib (Macugen, [OSI] Eyetech); and a pair of trials evaluating monthly ranibizumab versus ranibizumab plus PDT, called the SUMMIT series — the DENALI study in the United States, and its European counterpart, MONT BLANC. Also ongoing is the RADICAL trial, which includes double- and triple-therapy arms with reduced fluence PDT. A number of single-center, investigator sponsored trials and case series have also reported results.

Triple Therapy Series

We followed a prospective case series to examine the efficacy and safety of a triple combination of ranibizumab, reduced-duration PDT, and the corticosteroid dexamethasone over a 12-month period.²⁵

We chose dexamethasone for the anti-inflammatory component because it has 5 times the potency of triamcinolone²⁶ and it is short-acting, with faster clearance from the vitreous. Because it is administered in a pulse form, we believe it is less likely to result in glaucoma or cataract progression than has been seen with sustained-delivery triamcinolone or dexamethasone, and this has been borne out in our experience.^23,27

The study included 40 eyes of 40 patients with CNV secondary to AMD. Eyes with any of the following were excluded: intraocular surgery between treatments; previous PDT; previous anti-VEGF treatment; myocardial infarction within 2 months of baseline; stroke within 6 months of baseline; incomplete follow-up.

For initial treatment, all eyes received triple therapy: reduced-duration PDT, intravitreal dexamethasone 0.8 mg within 1 to 2 days after PDT, and intravitreal ranibizumab 0.5 mg within 3 to 5 days after administration of dexamethasone.

Reduced-duration PDT in this trial was administered for 42 seconds (rather than the usual 83 seconds) at 600 mW/cm², for a light dose of 25 J/cm².

Patients were followed for 12 months. Visual acuity testing and optical coherence tomography (OCT) were performed monthly, and fluorescein angiography was performed at months 3, 6, 9, and 12.

Injections of ranibizumab could be administered at examinations every 4 weeks if any of the following were observed: increase of OCT-measured central retinal thickness by more than 75 μm; decrease of visual acuity with any evidence of fluid on OCT; or evidence of new blood.

The entire triple therapy cycle was repeated if leakage was noted on fluorescein angiography.

Mean age of the patients was 80.2 years, and 58% were female. Lesions were occult in 40% of eyes, minimally classic in 25%, and classic in 35%. Mean baseline visual acuity was 20/200, and mean center point retinal thickness was 378 µm.

Results

No subjects discontinued the study, and compliance was excellent. Nine patients received a second round of triple therapy between 3 and 12 months. Thirteen subjects received a “booster” of ranibizumab, based on the study criteria, at 1 to 2 months after triple therapy. Five of these patients had also received the triple therapy cycle a second time.

At 12 months, 90% of study eyes improved by at least one line of visual acuity from baseline. Mean gain in visual acuity gain was 2.45 lines (Figure 1).

Mean Snellen visual acuity improved from approximately 20/200 to 20/80 by month 2 and to nearly 20/70 by month 12 (Figure 2 and 3).

Central retinal thickness improved from a baseline mean of 378 microns to a mean of 188 microns over the 12 month period, a decrease of 190 microns (P<0.0001).  The majority of the improvement in central retinal thickness was in the first 3 months (Figure 4).

Visual acuity improved in eyes with all lesion subtypes (Table 1). At least 75% of eyes in each subtype required only a single treatment. Overall, 78% of eyes received only one treatment, and 22% received one additional triple treatment.

Regarding safety, no cases of stroke, myocardial infarction, endophthalmitis, or intraocular pressure elevation above 25 mm Hg were seen. No cataract progression was observed. Retinal pigment epithelial tear occurred in two subjects.

Conclusion      

The encouraging results in this single-center, prospective, nonrandomized study demonstrate safety and the maintenance or increase of visual acuity outcomes, with reduced frequency of intravitreal treatment in comparison to available monotherapies.

It is not our intention to replace anti-VEGF monotherapy with combination therapy. Rather, with multiple approaches available for the treatment of CNV in AMD, therapy can be tailored to the individual patient. Some patients may do well with anti-VEGF monotherapy, while others may benefit from some combination of therapies. The evaluation of these combination treatments in prospective randomized clinical trials remains to be accomplished.

REFERENCES

1. Hughes MS. New combination approaches for the management of AMD. Paper presented at: Retina, held in conjunction with Hawaiian Eye 2007. Jan. 14-19, 2007. Kauai, Hawaii.
2. Lucentis [package insert]. South San Francisco, California: Genentech; 2007. Available at: http://www.gene.com/gene/products/information/tgr/lucentis/insert.jsp. Accessed January 17, 2008.
3. Macugen [package insert]. New York; (OSI)Eyetech; July 2006. Available at: http://www.macugen.com/macugenUSPI.pdf. Accessed January 17, 2008.
4. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr, Esquiabro M. 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.
5. Brown DM, Kaiser PK, Michels M, for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
6. Rosenfeld PJ, Brown DM, Heier JS, et al, for the the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
7. Zhu W, Mao Y, Zao Y, et al. Transplantation of vascular endothelial growth factor-transfected neuronal stem cells into the rat brain provides neuroprotection after transient focal ischemia. Neurosurgery. 2005;57:325-333.
8. Solerte SB, Ferrari E, Cuzzzoni G, et al. Decreased release of the angiogenic peptide vascular endothelial growth factor in Alzheimer’s disease. Dment Geriatr Cogn Disorder. 2005;19:1-10.
9. Yashuhara T, Singo T, Kobayashi K, et al. Neuroprotective effect of VEGF upon dopaminergic neurons in a rat model of Parkinson’s disease. Eur J Neuro. 2004;
10. Genentech “Dear Healthcare Provider” letter. Jan. 24, 2007. Available at: http://www.gene.com/gene/products/information/pdf/healthcare-provider-letter.pdf. Accessed January 16, 2008.
11. Kaiser PK. Verteporfin therapy in combination with triamcinolone: published studies investigating a potential synergistic effect. Curr Med Res Opin. 2005;21:705-713.
12. Jonas JB. Intravitreal triamcinolone acetonide for treatment of intraocular oedematous and neovascular diseases. Acta Ophthalmol Scand. 2005:83:645-663.
13. Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular agerelated macular degeneration. Can J Ophthalmol. 2005;40:352-368.
14. Jo N, et al. Am J Pathol 2006;168:2036-53.
15. Tatar O, et al. Retina 2007;27:713-23.
16. Saishin Y, et al. J Cell Physiol 2003;195:210-9.
17. Uckermann O, et al. J Pharmacol Exp Ther 2005;315:1036-45.
18. Heier JS, et al. Arch Ophthalmol 2006;124:1532-42.
19. Lazic R, Gabric N. Ophthalmology 2007;114:1179-85.
20. Spaide RF, et al. Ophthalmology 2003;110:1517-25.
21. Augustin AJ, Schmidt-Erfurth U. Ophthalmology 2006;113:14-22.
22. Liggett PE, et al. Am J Ophthalmol 2006;142:1072-4.
23. Augustin AJ, et al. Retina 2007;27:133-40.
24. Ladewig MS, et al. Graefes Arch Clin Exp Ophthalmol 2007;Aug 15 [e-pub ahead of print].
25. Hughes MS, Sang DN. Reduced-duration photodynamic therapy (PDT) combined with intravitreal dexamethasone and ranibizumab for exudative age-related macular degeneration. Poster presented at: American Society of Retina Specialists Annual Meeting; Palm Springs, California; December 1-5, 2007.
26. Hardman JG, et al, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill Book Co; 2001:1657,Table 60-2
27. Sivaprasad D, et al. Acta Ophthalmol Scand 2006;84:722-33.