submit to the journals

Photodynamic Therapy with Verteporfin in Age-related Macular Degeneration

US Sensory Disorders Review, 2006:7-12 DOI: http://doi.org/10.17925/USOR.2006.00.00.7
Received: January 10, 2011 Accepted: January 10, 2011

AMD is generally categorized as nonneovascular (dry) or neovascular (wet). Clinical findings of non-neovascular AMD include drusen, pigmentary changes, and atrophy of the retinal pigment epithelium with resultant gradual visual decline. Neovascular AMD occurs when choroidal neovascularization (CNV) penetrates through compromised areas of Bruch’s membrane and into the potential space between the retina and retinal pigment epithelium. Neovascularization can present with subretinal and intra-retinal edema, exudation, hemorrhage, and eventually a fibrovascular scar resulting in profound loss of central visual acuity. The vast majority of AMD related visual loss is caused by the neovascular form.2 With the aging US population, clinicians can expect to see an exponential increase in neovascular AMD over the next twenty years; in fact, it is estimated that one million individuals will develop neovascular AMD in the next five years in the US alone.3

Prior to 2000, patients with neovascular AMD had limited treatment options for subfoveal CNV. The Macular Photocoagulation Study (MPS) Group had proposed thermal laser for the treatment of subfoveal lesions.4 Although thermal laser was shown to reduce the risk of severe vision loss (≥6 lines from baseline), damage to central vision from the treatment itself was immediate, permanent, and difficult for patients to comprehend.This led to a search for alternative treatments such as photodynamic therapy (PDT), submacular surgery, and anti-angiogenesis drugs. PDT with verteporfin was the first of these new modalities to be shown to be effective in randomized controlled clinical trials and was approved by the US Food and Drug Administration (FDA) in 2000.

Verteporfin is a benzoporphyrin derivative that is administered via intravenous infusion over a ten-minute period at a concentration of 6mg/m2 of body surface area.Verteporfin is rapidly distributed throughout the body, bound to low-density lipoproteins (LDLs). Since neovascular tissue is rich in LDL receptors, verteporfin- LDL complexes preferentially accumulate in choroidal neovascular membranes.5,6 Fifteen minutes after administration, verteporfin is then activated in vivo with the application of 689nm non-thermal laser at an intensity of 600mW/cm2 for 83 seconds directly over the choroidal neovascular complex.Activation results in the formation of cytotoxic, free radicals that cause selective vasoconstriction, platelet aggregation, and fibrin clot formation in choroidal neovascular tissue resulting in vessel closure.5,6

The clinical efficacy of PDT with verteporfin for AMD has been evaluated in four large, randomized, double-blind, placebo-controlled studies. The treatment of AMD with photodynamic therapy (TAP) study showed a significant reduction in the risk of vision loss with PDT with verteporfin in patients with classic or classic plus occult subfoveal CNV. After 24 months, 53% of PDT recipients achieved the primary endpoint (<15 letters vision loss) versus 38% of those receiving placebo (p<0.001).

References:
  1. Bressler NM, Bressler SB, Fine SL, “Age-related macular degeneration”, Surv Ophthalmol (1988); 32 (6):pp. 375–413.
  2. Ferris III FL, Fine SL, Hyman L, “Age-related macular degeneration and blindness due to neovascular maculopathy”, Arch Ophthalmol (1984); 102:pp. 1,640–1,642.
  3. Bressler NM, Bressler SB, Congdon NG, et al.,“Potential public health impact on age-related eye disease study results:AREDS report no. 11”, Arch Ophthalmol (2003); 121:pp. 1,621–1,624.
  4. Macular Photocoagulation Study Group, “Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the macular photocoagulation study”, Arch Ophthalmol (1991); 109:pp. 1,242–1,257.
  5. Schmidt-Erfurth U, Hasan T, “Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macualar degeneration”, Surv Ophthalmol (2000); 45 (3):pp. 195–214.
  6. Scott LJ, Goa KL,“Verteporfin”, Drugs Aging (2000); 16:pp. 139–146.
  7. Bressler NM,“Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic Therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two year results of 2 randomized clinical trials-TAP report 2”, Arch Ophthalmol (2001); 119:pp. 198–207
  8. Treatment of Age-related macular degeneration with Photodynamic therapy Study Group, “Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one year results of 2 randomized clinical trials- TAP report” Arch Ophthalmol (1999); 117:pp. 1,329–1,345.
  9. Verteporfin in Photodynamic Therapy Study Group,“Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization:VIP report no. 2”, Am J Ophthalmol (2001); 131:pp. 541–560
  10. Bressler NM,“Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report no. 2”, Am J Ophthalmol (2002); 133:pp. 168–169
  11. Blinder KJ, Bradley S, Bressler NM, et al., “Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration:TAP and VIP report no. 1”, Am J Ophthalmol (2003); 136:pp. 407–418
  12. Azab M, Boyer DS, Bressler NM, “Visudyne in Minimally Classic Choroidal Neovascularization Study Group.Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial”, Arch Ophthalmol (2005); 123:pp. 448–457.
  13. Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al., “Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor”, Invest Ophthalmol Vis Sci (2003); 44:pp. 4,473–4,480.
  14. Spaide RF, Sorenson J, Maranan L,“Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization”, Ophthalmology (2005); Feb; 112(2):pp. 301–304.
  15. Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL, “The effects of intravitreal triamcinolone acetonide on experimental preretinal neovascularization”, Graefes Arch Clin Exp Ophthalmol (1993); 231:pp. 34–40.
  16. Ciulla TA,Criswell MH, Danis RP, Hill TE,“Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a lasertreated rat model”, Arch Ophthalmol (2001); 119:pp. 399–404.
  17. Penfold PL,Wen L,Madigan MC,et al.,“Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM- 1) expression of the ECV304 cell line: implications for macular degeneration”, Clin Exp Immunol (2000); 121:pp. 458–465.
  18. Wang YS, Friedrichs U, Eichler W, et al., “Inhibitory effects of triamcinolone acetonide on bFGF-induced migration and tube formation in choroidal microvascular endothelial cells”, Graefes Arch Clin Exp Ophthalmol (2002); 240:pp. 42–48.
  19. Rogers AH, Martidis A, Greenberg PB, Puliafito CA, “Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization”, Am J Ophthalmol (2002); 134:pp. 566–576.
  20. Danis RP, Ciulla TA, Pratt LM,Anliker W,“Intravitreal triamcinolone acetonide in exudative age-related macular degeneration”, Retina (2000); 20:pp. 244–250.
  21. Gillies MC, Simpson JM, Billson FA, et al.,“Safety of an intravitreal injection of triamcinolone: results from a randomized clinical trial”, Arch Ophthalmol (2004); 122:pp. 336–340.
  22. Jonas JB, Kreissig I, Hugger P, et al., “Intravitreal triamcinolone acetonide for exudative age related macular degeneration”, Br J Ophthalmol (2003); 87:pp. 462–468.
  23. Bucher RS, Hall E, Reed DM, et al., “Effect of intravitreal triamcinolone acetonide on susceptibility to experimental bacterial endophthalmitis and subsequent response to treatment”, Arch Ophthalmol (2005); May,123(5):pp. 649–653.
  24. Rosenfeld PJ, Rich RM, Lalwani GA, “Ranibizumab: Phase III Clinical Trial Results”, Ophthalmol Clin North Am (2006); Sep;19(3):pp. 361–372.
  25. “New data from two leading clinical studies show Lucentis® is first therapy to improve vision in patients with wet age-related macular degeneration (AMD)”, June 18, 2005, http://dominoext.novartis.com