Article Date: 5/1/2005

PEER REVIEWED
Verteporfin Patient Management Update
RUBIN KIM, MD  and CAROLINE R. BAUMAL, MD

In 2001 verteporfin (Visudyne) was approved by the Food and Drug Administration to be used as an agent for the technique of photodynamic therapy. This process is approved to treat specific types of choroidal neovascularization, secondary age-related macular degeneration, and pathologic myopia. Prior to its approval, laser photocoagulation was the only therapy studied and shown to treat specific types of CNV in the macular photocoagulation studies. However, it is only possible to treat a small percentage of eyes with laser photocoagulation, as this therapy was primarily effective in treating choroidal neovascularization (CNV) located outside of the fovea (extrafoveal or juxtafoveal) that is classic in configuration. Thus, laser photocoagulation is limited to treat only a small proportion of eyes that present with exudative age-related macular degeneration (AMD). The long-term prognosis after laser photocoagulation is also limited by a high rate of recurrent CNV after therapy. For this reason, the development of new strategies to treat AMD such as verteporfin with photodynamic therapy (PDT), has allowed treatment of more patients with this vision threatening disorder.

Figure 1. Angiographic and optical coherence tomography course of predominantly classic CNV in AMD treated with verteporfin PDT on 2 occasions.

TECHNIQUE OF PDT

Photodynamic therapy is a 2-step process. Initially, a photosensitizer must gain access to the target tissue. The second step involves activation of the photosensitizer by nonthermal light, which leads to thrombosis and photooxidation within the target tissue. For PDT of CNV, verteporfin is given intravenously to gain access to the CNV and is activated by a specific wavelength light to produce its ultimate effect of occlusion of CNV. While only recently approved for ophthalmology, PDT is not a new concept. It was initially investigated as a potential means to produce occlusion within vascular tumors in oncology. The posterior segment of the eye is uniquely suited for PDT due to the ease of access of light exposure with a fundus contact lens. Verteporfin is the only agent thus far approved to treat CNV in ophthalmology. The treatment parameters such as the length of light exposure, fluence of exposure light, and the duration between treatments were all based on preclinical and phase 1 and 2 studies. Subsequent to verteporfin with PDT approval, variations in the treatment parameters have been studied in an effort to optimize the effectiveness of verteporfin with PDT, and to assess whether it would be beneficial to treat other configurations of CNV or CNV secondary to other disorders.

Initially, the FDA approved PDT use for predominantly classic subfoveal CNV in eyes with AMD.1 Subsequently in August of 2001, the FDA expanded approval of verteporfin with PDT to include subfoveal CNV associated with pathologic myopia or ocular histoplasmosis.2 In 2004, the Centers for Medicare and Medicaid Services (CMS) approved coverage of subfoveal occult and minimally classic CNV lesions that were ¾4-disc areas with associated recent disease progression. Recent disease progression was defined as deterioration of visual acuity (VA) (loss of at least 5 letters on a standard eye chart), lesion growth of at least 1-disc area, or the appearance of blood associated with the lesion within 3 months of initial treatment.

VERTEPORFIN PDT STUDIES

The efficacy of verteporfin PDT in the treatment of subfoveal CNV has been evaluated in several large, multicenter studies to date. The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study group looked at the use of verteporfin vs. placebo in 609 patients from 22 centers throughout Europe and North America.1-3 Patients were included if they had a subfoveal CNV secondary to AMD with some classic component, the greatest linear lesion dimension of <5400 µm, and BCVA between 20/40 and 20/200 Snellen equivalent. Patients were treated with either verteporfin PDT or placebo and followed up at 3-month intervals for 2 years. Patients were retreated with verteporfin or placebo as often as every 3 months if the investigator determined that there was fluorescein leakage from the CNV on fluorescein angiography (FA). Patients were treated an average of 3.5 times in the first year and a total of 5 times by the end of the second year. Figure 1 demonstrates the angiographic and optical coherence tomography course of predominantly classic CNV in AMD treated with verteporfin PDT on 2 occasions.

The primary outcome measure was the number of eyes with loss of fewer than 15 letters of vision at 12 and 24 months. Ninety-four percent of the patients completed the 12-month evaluation. Two hundred and forty six (61%) of 402 eyes assigned to verteporfin PDT treatment vs. 96 (46%) of 207 eyes assigned to placebo lost fewer than 15 letters at 1 year. This difference was statistically significant demonstrating a treatment benefit from PDT with verteporfin compared to placebo. At 24 months, this treatment benefit was maintained with 62% in the verteporfin PDT treatment group vs. 47% in the placebo group losing fewer than 15 letters.

When subgroup analysis was performed, it was found that eyes with predominantly classic CNV lesions (defined as an area of classic CNV more than or equal to 50% of the entire lesion) demonstrated the most benefit with verteporfin PDT treatment. At 12 months 67% of the verteporfin PDT treated vs. 39% of placebo treated patients had lost fewer than 15 letters. This statistically significant difference was maintained at 24 months where 59% of verteporfin PDT treated vs. 31% of placebo treated patients lost fewer than 15 letters. For those patients with minimally classic CNV lesions, there was no statistically significant difference in vision between the verteporfin PDT treatment group and placebo groups.

In addition to the primary outcome measure of VA, FA findings and contrast sensitivity were better in the verteporfin PDT treatment group. These findings were maintained at the 12-month and 24-month visits. Fluorescein angiography findings and contrast sensitivity outcomes were improved not only in the predominately classic group, but also in the minimally classic group.4 The TAP report number 3 further analyzed the relationship between lesion composition and treatment effect and further supported the positive effect of verteporfin PDT for predominately classic lesions.5 It also suggested that not only lesion composition, but also lesion size might be an important factor in determining the beneficial visual effect of verteporfin PDT therapy.

Three hundred and twenty (92%) of the verteporfin PDT treated patients who completed the 24-month evaluation went on to enroll in an extension study.6 An average of 1.3 verteporfin PDT treatments were given between the 24-month and 36-month visits to the original group of patients that had predominately classic CNV. Visual acuity measures remained relatively stable for this group of patients during the third year and fifth year of follow-up, as compared with the second year of follow-up.

The Verteporfin in Photodynamic Therapy (VIP) Study was a multicenter, double-masked, placebo-controlled, randomized trial at 28 ophthalmology practices in Europe and North America.7 The study primarily evaluated patients with subfoveal CNV that lacked a classic component. Initially, the VIP study showed no statistically significant benefit to verteporfin PDT treatment at the 12-month visit with moderate vision loss occurring in 51% of the verteporfin PDT treated eyes and 54% of placebo eyes. However, at the 24-month visit, a statistically significant difference was seen with 54% of verteporfin PDT treated eyes vs. 67% of placebo eyes losing more than 15 letters. Additionally, the verteporfin treated eyes had a statistically significant lower rate of severe vision loss (>30 letters loss).

Further subgroup analysis was performed to look at the influence of lesion size and level of initial VA on the treatment benefit of verteporfin PDT. This revealed a greater effect of PDT therapy in eyes with CNV lesion size <4-disc areas or a VA score of less than 65 (approximate Snellen equivalent of 20/50 or worse).7 If either of these criteria were present, 49% of the verteporfin PDT treated vs. 75% of placebo eyes lost more than 15 letters (P<.001).

A retrospective analysis evaluated data from both the TAP and VIP studies to assess the effects of lesion composition, lesion size, and baseline VA on verteporfin treatment benefit.8 Baseline VA was not predictive of treatment outcome for any of the lesion types. Lesion size was a predictive factor in the magnitude of verteporfin treatment benefit for minimally classic CNV or occult CNV with no classic component. Smaller lesion size at <4-disc areas was associated with better outcomes. However, in predominately classic lesions treatment with the benefit of verteporfin PDT to reduce vision loss was maintained regardless of the lesion size studied.

The Verteporfin in Minimally Classic CNV Trial was designed to address the utility of verteporfin PDT for smaller minimally classic CNV lesions and to assess the possible benefit of lower light fluence rate compared to standard PDT treatment.9 Although complete study results have not been published, the preliminary findings seemed to indicate reduced moderate vision loss in patients with minimally classic lesions of smaller dimension (noted at
<6-disc areas). No statistically significant difference was noted between the standard fluence and reduced fluence PDT exposure groups at 12 months.

The Verteporfin with Altered (Delayed) Light in Occult CNV Study was designed to assess whether delaying the timing of light application to 30 minutes after the start of infusion rather than 15 minutes as in standard verteporfin PDT would improve visual and angiographic outcome for patients with subfoveal occult CNV with no classic component. Sixty patients were randomized to receive either standard or delayed PDT treatment. There was no significant difference in VA benefits or angiographic findings in either group, thus the standard 15-minute light application was recommended.

The Verteporfin Early Retreatment (VER) Trial was initiated to assess whether earlier PDT retreatment intervals (every 1.5 months during the first 6 months) compared with the standard 3-month intervals would improve treatment outcomes for patients receiving PDT for predominantly classic CNV.10 At 12 months, mean VA had decreased by 14.9 letters from baseline in the early PDT retreatment group and 13.6 letters for the standard PDT group. This effect was not statistically significant and thus, the VER did not reveal a visual benefit from earlier timing in repeat PDT retreatments using these parameters.

The Japanese AMD Trial studied 64 Japanese AMD patients to assess the safety and efficacy of PDT.11 The vision effects appeared to be better in these Japanese patients then that seen in the TAP studies. There was a mean improvement in median VA score from 50.0 (20/100) at baseline to 56.5 (20/80 [+2]) at the 12-month visit. No additional safety concerns were seen compared with the TAP studies.

Overall, PDT with verteporfin had a low incidence of adverse events in the TAP and VIP studies. One clinically relevant ocular adverse event was the incidence of visual disturbance. Acute severe visual acuity decrease (ASVD), defined as a vision loss equivalent to >4 lines within 7 days of treatment, occurred in 13 out of 948 patients in the TAP and VIP trials.12 Eleven of these events occurred after the first treatment. Large CNV lesion size, >4-disc areas, and pretreatment vision better than 20/50 were factors associated with ASVD. Visual acuity eventually improved to some degree in 10 of these patients. Investigators
concluded that the risks of ASVD due to verteporfin PDT did not outweigh the overall long-term potential treatment benefits; however, patients should be informed of the possibility of ASVD. Other systemic adverse events included injection site reactions, photosensitivity reactions, and infusion-related back pain.13 Most of these reactions were transient, reversible, and mild. Many of these events can be avoided with proper monitored medication infusion and patient education to avoid sun exposure for the prescribed time interval after therapy.

The Verteporfin Therapy in Age-Related Macular Degeneration (VAM) was an open-label, multicenter study that gathered safety data on PDT on a total of 4051 patients receiving 6701 treatments.14 The VAM trial found no new safety concerns and further confirmed the low incidence of systemic and ocular adverse events as found in the TAP and VIP trials.

In December 2004, pegaptanib (Macugen, Eyetech Pharmaceuticals) was approved by the FDA as a new therapy for exudative AMD. This agent was designed to block the activity of extracellular vascular endothelial growth factor (VEGF). The rationale is based on the finding that VEGF appears to play a role in ocular disorders characterized by neovascularization and increased vascular permeability, such as noted in exudative AMD. The combined results of 2 prospective, randomized, multicenter, controlled clinical trials demonstrated the efficacy of intravitreally-injected pegaptanib to maintain or improve vision when compared to sham intravitreal injection (essentially no drug therapy).15 The prespecified study endpoint was the proportion of patients who lost fewer than 15 letters of VA (defined as moderate loss). A statistically significant drug effect was attained with intravitreal pegaptanib injection every 6 weeks over 48 weeks in eyes with predominantly classic, minimally classic, and occult CNV. No direct comparative study has been made on the ocular outcomes of patients treated with verteporfin PDT vs. pegaptanib. It is notable, at the discretion of the treating physician, that the use of PDT with verteporfin was permitted during the study in eyes with predominantly classic CNV lesions as per the FDA approved product labeling at that time. Further subgroup analysis and results from the pegaptanib studies and experience beyond the initial 1-year preliminary study will provide more information about the optimal ocular features that will best respond to this therapy compared to verteporfin and other new therapies. Combination therapies involving either of these agents with other experimental therapies may also provide further optimization of visual results in AMD.

CONCLUSIONS

Verteporfin PDT has played a critical role as a long awaited new modality to treat CNV in exudative AMD with specified features and pathologic myopia. It may also be able to treat other disorders with subfoveal CNV that lack any treatment options, although it has not specifically been approved for other indications. Based on its mechanism of action, further investigation of PDT to treat other causes of ocular neovascularization or subtypes of exudative AMD may be indicated. The ability to enhance the effectiveness of PDT by varying verteporfin treatment parameters or by combination with other agents, such as corticosteroids, requires further investigation. Continued research and therapeutic developments for AMD will lead to more options for treating individuals with this common and potentially visually devastating disorder.

REFERENCES

1. 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: one-year results of 2 randomized clinical trials- TAP report 1. Arch Ophthalmol. 1999;117:1329-1345.

2. Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial--VIP report no. 1. Ophthalmology. 2001;108:841-52.

3. 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;119:198-207.

4. Rubin GS, Bressler NM, and the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Effects of verteporfin therapy on contrast sensitivity: results from the Treatment of Age-Related Macular Degeneration With Phtodynamic therapy (TAP) investigation- TAP report no. 4. Retina. 2002;22:536-544.

5. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: additional information regarding baseline lesion composition's impact on vision outcomes- TAP report no. 3. Arch Ophthalmol. 2002; 20:1443-1454.

6. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials- TAP report no. 5. Arch Ophthalmol. 2002;120:1307-1314.

7. 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- Verteporfin In Photodynamic Therapy report 2. Am J Ophthalmol. 2001;131:541-560.

8. Blinder KJ, Bradley S, Bressler NM, et al, for the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) and Verteporfin In Photodynamic Therapy (VIP) Study Groups. 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;136:407-418.

9. Bressler NM, Rosenfeld PJ, Lim JI, and VIM Study Group. A phase II placebo-controlled, double-masked, randomized trial- verteporfin in minimally classic CNV due to AMD (VIM) [abstract]. Invest Ophthalmol Vis Sci. 2003;44:E-Abstract 1100.

10. Stur M. Verteporfin Early Retreatment (VER)- 12-month results of a phase IIIb controlled clinical trial [abstract]. Invest Ophthalmol Vis Sci. 2004;45:E-Abstract 2275. ARVO. 2004

11. Japanese Age-Related Macular Degeneration Trial (JAT) Study Group. Japanese age-related macular degeneration trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Am J Ophthalmol. 2003;136:1049-61.

12. Arnold JJ, Blinder KJ, Bressler NM, et al, for the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Acute severe visual acuity decrease after photodynamic therapy with verteporfin: case reports from randomized clinical trials- TAP and VIP report no. 3. Am J Ophthalmol. 2004;137:682-696.

13. Azab M, Benchaboune M, Blinder KJ, et al, for the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: meta-analysis of 2-year safety results in three randomized clinical trials: Treatment of Age-Related Macular Degeneration With Photodynamic Therapy and Verteporfin In Photodynamic Therapy study report no. 4. Retina. 2004;24:1-12.

14. Bressler NM, for the VAM Study Writing Committee. Verteporfin therapy in age-related macular degeneration (VAM): an open-label multicenter photodynamic therapy study of 4,435 patients. Retina 2004;24:512-520.

15. Gragoudas ES, Adamis AA, Cunningham E, Feinsod M, Guyer DR, for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. N Engl J Med. 2004;351;2805-2816.

From New England Eye Center, Boston, MA. None of the authors has any financial interest in the information discussed in this article.

 


Retinal Physician, Issue: May 2005