The limited number of currently approved

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1 CLINICAL TRIALS OF VERTEPORFIN AND PEGAPTANIB: WHAT ARE THE RESULTS? * William F. Mieler, MD ABSTRACT Currently available treatment options for the management of choroidal neovascularization (CNV) in age-related macular degeneration that have gone through multicenter clinical trial testing include thermal laser photocoagulation, photodynamic therapy (PDT) with verteporfin, intravitreal antivascular endothelial growth factor (VEGF) injections with pegaptanib, and submacular surgery. Although the limited number of approved therapies invites direct comparison, such an approach is not totally reliable because of differing inclusion and exclusion criteria utilized in the studies, along with a potentially vast array of unknown factors that cannot be fully controlled. As an alternative to a direct comparison, this article presents a side-by-side evaluation of 1-year vision outcome data from the controlled clinical trials of PDT with verteporfin and anti- VEGF therapy with pegaptanib. Reviewing the data in this format underscores the difference from baseline for each treatment versus placebo or sham, and it may help the clinician reach a decision as to which therapy to consider when the next patient with CNV presents for treatment. (Adv Stud Ophthalmol. 2005;2(3):88-93) *This article is based on a roundtable symposium held in Whistler, British Columbia, Canada, on August 6, Professor and Chairman, Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois. Address correspondence to: William F. Mieler, MD, Professor and Chairman, Department of Ophthalmology and Visual Science, University of Chicago Hospitals, 5801 South Maryland Avenue, S-209, Chicago, IL wmieler@uchicago.edu. The limited number of currently approved therapies for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) invites direct comparison of results from clinical trials evaluating these treatments, in addition to historical comparisons. However, such an approach is not totally accurate because inclusion and exclusion criteria are not precisely the same in the clinical trials at issue and because CNV in AMD has a variable outcome and different treatment effects that are influenced by several unknown factors, thereby making historical comparisons tenuous and/or hazardous. A better approach is a side-by-side evaluation of clinical trial data that represents how and what to consider for the next patient with AMD-related CNV who seeks treatment. TREATMENT OPTIONS Currently available, clinically proven treatment options for the management of CNV in AMD include thermal laser photocoagulation, photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis Pharma AG; Basel, Switzerland), and intravitreal antivascular endothelial growth factor (VEGF) injections of pegaptanib (Macugen; Eyetech Pharmaceuticals, Inc and Pfizer Inc; New York, NY). Whereas submacular surgery also has been studied, it has not been shown to be effective in the management of patients with CNV secondary to AMD. The choice of a particular therapy depends on several important factors, including lesion size, location, and composition, evidence of recent disease progression, and visual acuity. In general, the larger the lesion, the worse the visual acuity. 88 Vol. 2, No. 3 December 2005

2 Neovascular lesions that are predominantly choroidal on fluorescein angiography may be extrafoveal, juxtafoveal, or subfoveal. Extrafoveal lesions are best treated by thermal laser photocoagulation, as thoroughly studied and reported in the Macular Photocoagulation Study (MPS). 1 Juxtafoveal lesions can be treated with thermal laser photocoagulation, PDT with verteporfin, or pegaptanib. The choice of therapy for subfoveal lesions requires further evaluation with respect to lesion size and composition, recent disease progression, and baseline level of visual acuity. Accordingly, these lesions are the primary focus of this article. ONE-YEAR RESULTS WITH VERTEPORFIN AND PEGAPTANIB A review of trials evaluating verteporfin therapy and pegaptanib reveals that both agents yielded similar results at 1 year in reducing the risk of vision loss and were superior to placebo or sham injections in this regard. ALL CHOROIDAL NEOVASCULAR LESIONS Data for 4 vision outcomes at 1 year for all CNV lesions enrolled in the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) investigation, 2 the Verteporfin in Photodynamic Therapy (VIP) study, 3 and the VEGF Inhibition Study in Ocular Neovascularization 4,5 (VISION) are shown in Table 1. The primary endpoint in the TAP investigation and VISION was the percentage of patients losing fewer than 15 letters or 3 lines of vision (moderate vision loss). Other outcomes were the percentage of patients losing fewer than 30 letters or 6 lines of vision (severe vision loss), the percentage of patients gaining 15 letters or more, and the mean change in visual acuity in letters from baseline. In the TAP investigation and VISION, the difference between treated eyes and controls was similar for the primary endpoint and other vision outcomes. RESULTS BY LESION COMPOSITION AND/OR SIZE Although the 1-year data demonstrate similar efficacy for verteporfin and pegaptanib for all CNV lesions, it is necessary to examine the data by lesion composition and to determine whether it influences the benefits of therapy with each agent. As shown in Table 2, the benefits of verteporfin versus placebo in the initial TAP investigation 2 and a subsequent TAP Study Group 6 investigation exploring lesion composition at baseline appear to be driven by predominantly classic lesions, particularly with respect to the primary Table 1. One-Year Efficacy Results for All Choroidal Neovascular Lesions in TAP, VIP, and VISION TAP Investigation 2 VIP Study 3 VISION 4,5 Verteporfin Placebo Verteporfin Placebo Pegaptanib* Sham (n = 402) (n = 207) Difference (n = 225) (n = 114) Difference (n = 294) (n = 296) Difference Loss of < Loss of < Gain Mean VA change from baseline TAP = Treatment of Age-Related Macular Degeneration with Photodynamic Therapy; VA = visual acuity; VIP = Verteporfin in Photodynamic Therapy; VISION = Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization. *0.3 mg; Primary endpoint; P <.001; letters. Data from Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2 ; Verteporfin in Photodynamic Therapy Study Group 3 ; FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting 4 ; and Gragoudas et al. 5 Advanced Studies in Ophthalmology 89

3 endpoint, in which the 27.5% difference between treated lesions and controls was statistically significant. The 12% difference between predominantly classic lesions treated with pegaptanib and controls was not statistically significant for the primary endpoint 4,5 and reflected a less pronounced impact of lesion composition on the benefits of therapy than verteporfin versus placebo. 2,6 One-year treatment results in minimally classic lesions at baseline in the TAP investigation, 2,6 VISION, 4,5 and the Visudyne in Minimally Classic Choroidal Neovascularization 7 (VIM) study are shown in Table 3. Differences between treated and control lesions were statistically significant for the primary endpoint in VISION only. The difference between treatment and controls was very small in the TAP investigation, but it Table 2. One-Year Efficacy Results for Predominantly Classic Lesions at Baseline in TAP and VISION TAP Investigation 2,6 VISION 4,5 Verteporfin Placebo Pegaptanib* Sham Predominantly Classic (n = 159) (n = 83) Difference (n = 72) (n = 76) Difference Loss of < Loss of < Gain NA NA NA Mean VA change from baseline TAP = Treatment of Age-Related Macular Degeneration with Photodynamic Therapy; VA = visual acuity; VISION = Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization. *0.3 mg; Primary endpoint; P <.001; P =.15; letters. Data from Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2 ; FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting 4 ; and Gragoudas et al 5 ; and Bressler et al. 6 Table 3. One-Year Efficacy Results for Minimally Classic Lesions at Baseline in TAP, VIM, and VISION VIM Study 7 * TAP Investigation 2,6 (Standard Fluence) VISION 4,5 * Minimally Verteporfin Placebo Verteporfin Placebo Pegaptanib Sham Classic (n = 202) (n = 104) Difference (n = 36) (n = 40) Difference (n = 110) (n = 100) Difference Loss of < Loss of < Gain NA NA NA Mean VA change from baseline # TAP = Treatment of Age-Related Macular Degeneration with Photodynamic Therapy; VA = visual acuity; VIM = Visudyne in Minimally Classic Choroidal Neovascularization; VISION = Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization. *With recent disease progression; 0.3 mg; Primary endpoint; P =.92; P =.08; P <.001; # letters. Data from Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 2 ; FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting 4 ; Gragoudas et al 5 ; Bressler et al 6 ; and Azab et al Vol. 2, No. 3 December 2005

4 was substantial in the VIM study (19%) and VISION (22%). The minimally classic lesions in both of these studies were lesions that had shown recent disease progression or had changes in visual acuity. One-year treatment results in occult with no classic lesions and recent disease progression in the VIP study 3 and VISION 4,5 are shown in Table 4. Although the difference between verteporfin and placebo was only 4% for moderate vision loss and 10.3% for severe vision loss, it increased substantially to 15% for moderate and severe vision loss when lesion size ( 4 MPS disc areas) and visual acuity ( 20/50-1) at presentation were taken into account. 3 The difference in mean visual acuity change from baseline also increased from -5.2 to Taken together, these findings suggest benefit of verteporfin treatment versus placebo for smaller occult lesions or lesions with lower levels of visual acuity. Like the initial TAP 2 investigation, which comprised 2 placebo-controlled, randomized clinical trials, VISION 4,5 comprised 2 concurrent, prospective, controlled, randomized clinical trials. A combined analysis of the VISION data, with estimates based on briefing documents reviewed by the Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee, 4 revealed that significantly more patients with small lesions (<4 MPS disc areas) who were treated with pegaptanib lost fewer than 15 letters at 54 weeks than patients with small lesions who received sham injections (71% vs 50%; P <.002). Response rates at 54 weeks among patients with lesions of 4 or more MPS disc areas were 68% for those receiving pegaptanib injections and 60% for those receiving sham injections, a difference that was not statistically significant (P =.25). Although VISION was not driven by lesion size, the response to pegaptanib injections versus sham injections was more impressive among patients with smaller lesions. CONCLUSIONS The TAP investigations demonstrated that verteporfin resulted in a significant 15% difference from placebo for the primary endpoint (losing <15 letters) in some classic CNV lesions (ie, predominantly classic and minimally classic lesions). A subgroup analysis suggested that benefits of therapy were driven by predominantly classic lesions (before lesion size was taken into consideration) with a 27.5% difference between verteporfin and placebo for the primary endpoint. The VIM study showed that verteporfin resulted in a 19% difference from placebo for the primary endpoint in minimally classic lesions of 6 or less MPS disc areas. The VIP study demonstrated that verteporfin resulted in a 4% difference from placebo for the primary endpoint at 1 year. However, the totality of other outcomes suggested a treatment benefit for smaller lesions or those with lower levels of visual acuity. These other outcomes included a 15% difference in loss of fewer than 15 letters at 2 years; 15% and 27% differences at 1 and 2 years, respectively, for a loss of fewer than 30 letters; and visual acuity of less than 20/200 and mean visual acuity change at 1 and 2 years. VISION demonstrated that pegaptanib resulted in Table 4. One-Year Efficacy Results for Occult with No Classic Lesions and Recent Disease Progression in VIP and VISION VIP Study 3 VISION 4,5 Verteporfin Placebo Pegaptanib* Sham Occult (n = 166) (n = 92) Difference (n = 112) (n = 120) Difference Loss of < Loss of < Gain NA NA NA Mean VA change from baseline VA = visual acuity; VIP = Verteporfin in Photodynamic Therapy; VISION = Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization. *0.3 mg; Primary endpoint; P =.10; P =.14; letters. Data from Verteporfin in Photodynamic Therapy Study Group 3 ; FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting 4 ; and Gragoudas et al. 5 Advanced Studies in Ophthalmology 91

5 a significant 15% difference from sham for the primary endpoint (losing <15 letters at 1 year) in all CNV lesions; a 12% difference for predominantly classic lesions; a significant 22% difference in minimally classic lesions and recent disease progression; a 10% difference in occult with no classic lesions and recent disease progression; and an 8% difference for lesions of 4 or more MPS disc areas. Thus far, no data have been published on pegaptanib with respect to lesion size and lesion composition. DISCUSSION 1-YEAR AND 2-YEAR OUTCOMES Dr Bressler: The 2-year data from the PDT trials that Dr Mieler discussed showed that the overall results were similar to the 1-year results, although the numbers changed a bit. The 2-year results for occult with no classic lesions gave us more confidence in the data because of the sustained or even increased benefits. However, we don t have any published data yet on the 2-year outcomes from studies evaluating pegaptanib injections. How do you deal with that in your practice? Dr MacCumber: There is some question regarding the pegaptanib data for occult with no classic lesions at the 2-year endpoint where the effect was not statistically significant in VISION s American trial. 4,5 However, if you look at other time points, I believe there was some benefit. It may not be fair to look at the 2-year endpoint alone. Dr Bressler: We don t have the information in front of us because it wasn t published, except as an abstract. The pegaptanib trial was not designed to assess efficacy at 2 years. The efficacy at 1 year was avoiding 3-line loss (or secondary outcomes, for example, of avoiding 6-line loss). There was a different design in year 2. The investigators rerandomized the patients and asked a different question. Not, Is it better than placebo? But, If we stop pegaptanib until a 15- or more letter decrease occurs, does that lead to a better or worse outcome than if we continue pegaptanib? They kept 50 of the 250 patients assigned to placebo on placebo and continued sham injections, and stopped therapy in another 50 patients, reinstating placebo if there was a loss of 15 or more letters. The remaining 150 subjects originally assigned to placebo also stopped injections unless there was a loss of 15 or more letters, but if such a decline occurred, these remaining 150 were assigned to a 0.3- mg, 1-mg, or 3-mg dose of pegaptanib. As a result, we have only 100 people on placebo to compare to individuals who continued on 0.3 mg pegaptanib, not 250; that is why we lost some ability to ask the efficacy question in the second year. The VISION trial wasn t designed to evaluate efficacy of pegaptanib versus placebo in the second year of the trial. Does that influence your interpretation at all? If not, why not? And if so, why? Dr Klein: I find the 2-year pegaptanib results difficult to deal with in terms of applying them to our clinical practice. I prefer an approach that incorporates the individual s response to therapy in making decisions regarding continuation of injections. Dr Bressler: Do you think it s fair to say that we have very solid evidence after 1 year, but not the same solid evidence about efficacy at 2 years? Dr Klein: Yes. I agree with that. Dr Olsen: I also agree with those statements. I think the 1-year data are solid. I haven t been to that point with any of my patients yet, but I would be comfortable continuing with the 2-year treatment. As you all know, things are changing rapidly and new scenarios may unfold before we have to make that decision. Dr Bressler: Then it may not make a difference. Maybe all we needed was 1-year data for that. Dr Mieler: I would tend to agree. With the products coming out on the market, it may have less of an impact. Certainly, the data suggest that patients who receive 2 full years of therapy fare better than patients who are treated for 1 year or those who have a discontinuance of their treatment, but I agree that the data are not based on a large number of patients. Dr Bressler: So they fare better in terms of that first event of a 15-letter loss. Dr Mieler: Correct. Dr Bressler: We don t have strong data to know if the 3-line loss or 6-line loss would have led to the same difference if we had continued all of the people on placebo. Dr Mieler: That s absolutely correct. LESION TYPE AND SIZE Dr Olsen: We ve published some work on the frequency of lesion types in exudative AMD. 8 We found that 73% of the subfoveal lesions were lesions with progression. There is a key word in the differentiation of this subgroup. If you use the word or that is, lesions that are less than 4 MPS disc areas or visual acuity is 20/50-1 or worse that category includes approxi- 92 Vol. 2, No. 3 December 2005

6 mately 94% of this group. On the other hand, if you use the word and the size of the lesion is less than or equal to 4 MPS disc areas and visual acuity is 20/50-1 or better it cuts the percentage to 47% of patients. When one looks at the data Dr Mieler reviewed the occult lesions that show progression with lesion size less than 4 MPS disc areas and visual acuity is less than 20/50-1 this is the group that did exceptionally well with PDT. In my practice, that is the group for which I recommend PDT. Given these PDT data and the pegaptanib data, I will use pegaptanib in cases where the lesion fits into the or category; that is, lesions that have large lesion size or better visual acuity, such as a large occult lesion with good central acuity. Dr Bressler: Do we have data from the pegaptanib trials for large lesions with visual acuity of less than 20/50 and large lesions with good vision? Dr Mieler: We don t have the final data in that regard. We d like to see more to feel really comfortable that pegaptanib is truly more effective than verteporfin therapy, but the data have not been fully released. Dr Bressler: I consider pegaptanib in large lesions, but I don t know the data yet. Maybe, like PDT, it doesn t work in these cases, or maybe it does. Dr Olsen: At that point, you have to weigh the potential risks of each one of those treatments for the particular eye you are treating. Dr Klein: We know that larger occult or minimally classic lesions are less likely to benefit from PDT, possibly for 2 reasons. One is that tissue damage may be more likely to occur when treating these large lesions. A second reason is the better natural history of large occult and minimally classic lesions compared to large classic lesions. If we were to guess without having the actual data pegaptanib may be better for those larger lesions because there would be no direct tissue damage. However, we don t know this. It may be difficult for pegaptanib to exert a treatment effect in this group considering the natural history. Dr Bressler: That s a good point because you get away from increasing risks that may be associated with increasing spot size with PDT. Instead, you are giving the same injection with pegaptanib whether it s a small lesion or a large lesion. I also agree that the larger the lesions are (when not predominantly classic), the less likely they are to deteriorate if the patient has relatively good vision to start with. This makes it harder to have a treatment that causes improvement. Dr MacCumber: I think it s particularly difficult to compare verteporfin PDT with pegaptanib for predominantly classic lesions because some eyes also were treated with PDT in the VISION trial. In the North American trial, approximately 65% of those eyes got at least 1 PDT treatment and, in the international trial, approximately 40% got at least 1 PDT treatment. Dr Bressler: That s one of many reasons why you cannot consider this a head-to-head trial. You just say, Here are all of our data on PDT, and here are all of our data on pegaptanib injections so far. Then we have to come to some conclusion about what treatment to recommend for the next patient walking in. REFERENCES 1. 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: Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized clinical trials-tap report 1. Arch Ophthalmol. 1999;117: 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: FDA Dermatologic and Ophthalmic Drugs Advisory Committee Meeting. August 27, Available at: mmittee/stories/082704_macugenr.htm. Accessed August 12, Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351: Bressler NM, Arnold J, Benchaboune M, et al. 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;120: Azab M, Boyer DS, Bressler NM, et al. 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: Olsen TW, Feng X, Kasper TJ, et al. Fluorescein angiographic lesion type frequency in neovascular age-related macular degeneration. Ophthalmology. 2004;111: Advanced Studies in Ophthalmology 93