Pegaptanib Intramers: and•Aptamers38 chapter

0.3–mg pegaptanib sodium (n=294) Usual care (n=296)

Figure 38.2  Proportion of subjects in the VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) trials who maintained or gained visual acuity at 54 weeks. Reproduced with permission from Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 2005;40:352–368.

losing 30 letters or proceeding to legal blindness (visual acuity 20/200). Treatment efficacy was also assessed anatomically through fluorescein angiography and fundus photography.34

In the combined trials, 1186 subjects received at least one study treatment and were included in subsequent analyses.34 Subjects received an average of 8.5 of 9 possible injections. All three pegaptanib doses were superior to sham for the principal endpoint with 70%, 71%, and 65% of responders in the 0.3-mg (P < 0.001), 1-mg (P < 0.001), and 3-mg (P < 0.03) groups respectively compared to 55% assigned to sham. Similar results were obtained using last observation carried forward or observed data. The approved 0.3-mg dose was the lowest effective dose, therefore, further discussion is limited to that dose. Pegaptanib was superior to sham in the proportion of subjects maintaining or gaining 5, 10, or 15 lines of vision (Figure 38.2).35 Furthermore, subjects receiving pegaptanib were less likely to have severe vision loss, defined as 30 letters (10 versus 22%, P < 0.001), or progress to legal blindness in the treated eye (38% versus 56%, P < 0.001). The effectiveness of pegaptanib was evident as early as the first study visit after the first injection (week 6), and it increased over time up to week 54, as measured by the mean loss of visual acuity from baseline to each study visit as compared with that in the sham group (P < 0.002). The mean loss in visual acuity at week 54 was –7.95 letters for the pegaptanib 0.3-mg group compared to –15.05 letters for sham-treated subjects (P < 0.05), representing a 47% relative difference (Figure 38.3).35 The treatment effect was independent of angiographic subtype, sex, age, baseline visual acuity, race, or iris color and was present despite the higher rate of use of PDT among patients receiving sham injections.35 In multivariate analyses based on the inclusion of these factors, as well as prior PDT usage, smoking status, presence of subretinal hemorrhage, lipid, visual acuity better in the fellow eye than study eye, and >3 lines of previous visual acuity loss, only treatment with 0.3-mg pegaptanib significantly affected treatment response (P = 0.0003).35

After the first year of the V.I.S.I.O.N. trials, subjects who elected to remain in the study were re-randomized for an additional 48 weeks.36 Those already receiving pegaptanib were randomized either to continue their respective pegaptanib dose or to receive sham injections. Subjects initially receiving sham injections were re-randomized to sham or one of the three pegaptanib doses. Overall, 1053 subjects were rerandomized; 941 subjects (89%) were assessed at week 102, having received an average of 15.7 injections (92% of a possible 17) over 2 years. Of those subjects receiving 0.3 mg pegaptanib during the second year, 59% (78/133) lost <15 letters while the mean loss in visual acuity was

Time (weeks)

Figure 38.3  Mean change in visual acuity at week 54 in subjects in the VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) trials who received 0.3-mg pegaptanib sodium or sham.

Reproduced with permission from Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 2005;40:352–368.

Patient treatment year 1– year 2

Figure 38.4  Mean visual acuity from week 54 to week 102 in the year-2 extension of the VEGF Inhibition Study in Ocular

Neovascularization (V.I.S.I.O.N.) trials. Reproduced with permission from Chakravarthy U, Adamis AP, Cunningham ET Jr et al. Year 2 efficacy results of two randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 2006;113(9):1508.e1–25.

9.4 letters. For those receiving sham injections over 2 years or randomized to discontinue sham in the second year, 45% (48/107) lost <15 letters, and mean visual acuity loss was 17 letters (P < 0.05 for both comparisons). (Figure 38.4) There were 21 cases of 3-line loss among subjects continuing pegaptanib 0.3 mg for 2 years versus 35 cases in those randomized to sham after 1 year of therapy (P < 0.05).36 Ten percent of pegaptanib-treated patients gained 3 lines of vision after 2 years. The percentage of patients gaining vision was higher for patients who received 2 years of treatment with 0.3-mg pegaptanib than for patients receiving usual care36 (Figure 38.5).

Subgroup analyses of the V.I.S.I.O.N. trials as well as case-series reports have suggested that providing treatment with pegaptanib early in the course of neovascular AMD may allow for better outcomes.37–39

DIABETIC RETINOPATHY

A randomized, sham-controlled, double-masked, dose-finding, phase II trial was performed to evaluate the efficacy and safety of pegaptanib for treatment of diabetic macular edema (DME).40 This trial enrolled 172

Diseases Retinal in Mechanisms and Drugs • 4 section

Patient treatment year 2

subjects 18 years and older with type 1 or type 2 diabetes. Entry criteria included best corrected visual acuity in the study eye from 20/50 to 20/320 and macular edema in the study eye involving the center of the macula, as confirmed by optical coherence tomography (OCT), together with leakage from microaneurysms, retinal telangiectasis, or both, demonstrable on fluorescein angiography. Subjects with a history of panretinal or focal photocoagulation or other retinal treatments within the previous 6 months were excluded.40

Subjects were randomized to three different doses of pegaptanib (0.3, 1, or 3 mg) or sham injections, stratified by study site, size of the thickened retina area (2.5 disc areas versus >2.5 disc areas) and baseline visual acuity (letter score 58 versus <58).40 Injections were given at baseline, week 6, and week 12 for a minimum of three injections, followed by additional injections given every 6 weeks up to week 30 (for a maximum of six injections) at the discretion of the investigators. In all, 169 subjects received at least one study treatment, with more than 90% of subjects completing the study; 49% of the pegaptanib-treated subjects received the maximal number of injections.40

At week 36, the mean change in visual acuity from baseline was +4.7, +4.7, and +1.1 for 0.3-, 1-, and 3-mg groups, respectively, versus −0.4 letters for the sham group (P = 0.04, 0.05, and 0.55, respectively). As in the V.I.S.I.O.N. trials for neovascular AMD the 0.3-mg dose was the lowest efficacious dose. The median visual acuity was significantly better in the 0.3-mg group compared with sham (20/50 versus 20/63, P = 0.04), as was the percentage of subjects maintaining or gaining vision (Figure 38.6).40 Pegaptanib treatment was also associated with improvements in macular edema as determined by mean changes in retinal thickness of the center point from baseline to week 36 (Table 38.1).40 Although there was some improvement in all three pegaptanib groups, only the 0.3-mg group was significantly better when compared with sham (−68.0 µm versus +3.7 µm, P = 0.02). In addition, more subjects in the pegaptanib-treated groups had absolute decreases of 75 µm, 100 µm, and 200 µm in macular edema when compared with sham. Benefits in the 0.3-mg group were particularly evident, with 49% showing a decrease of 75 µm in the center point of the central subfield compared with 19% in the sham group (P = 0.008) and 42% showing a decrease of 100 µm compared with 16% in the sham arm (P = 0.02). (Table 38.1). Both visual and anatomical benefits were achieved with less need for laser photocoagulation. Twenty-five percent of subjects receiving 0.3 mg pegaptanib required intervention with photocoagulation compared to 48% of those receiving sham (P = 0.042).40

Figure 38.6  Percentage of subjects maintaining or gaining visual acuity from baseline to week 36 in the Macugen for DME phase II trial (intention-to-treat population, n = 172 (missing data for one patient each in the 1-mg and sham groups)). *P < 0.05; †P < 0.01. Reproduced with permission from Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112:1747–1757.

Regarding proliferative diabetic retinopathy, a retrospective analysis of subjects enrolled in the phase II DME trial was conducted to evaluate the effects of pegaptanib on diabetic retinal neovascularization based on evidence that VEGF plays a prominent role in the pathogenesis of this condition.41,42 A review of all subjects identified 19 of 172 who had retinal neovascularization in the study eye at study baseline; 4 subjects also had retinal neovascularization in the fellow eye.43 Of these 19 subjects, there was 1 exclusion due to recent scatter photocoagulation therapy and 2 exclusions for incomplete follow-up. In the remaining cohort of 16 subjects, 8 had prior photocoagulation more than 6 months prior to the study and 1 had photocoagulation during the study.43 Thirteen of these subjects had received pegaptanib, while the remaining 3 subjects received sham injections.43 Eight of 13 (61%) subjects in the pegaptanib group, including the subject receiving photocoagulation in follow-up, had regression of neovascularization demonstrated by fundus photography and/or angiography at 36 weeks. In contrast, there was no neovascular regression in any of the 3 eyes in the sham group or in the 4 fellow eyes of subjects receiving pegaptanib. After the discontinuation of pegaptanib, there was recurrence of neovascularization between weeks 36 and 52 in 3 of the 8 subjects who originally responded to pegaptanib, including the subject receiving photocoagulation (Figure 38.7).43 These results were not only supportive of a therapeutic benefit for pegaptanib in the treatment of proliferative diabetic retinopathy, but suggested further that such benefit can be sustained following discontinuation of therapy in a sizable proportion of subjects.

These findings were later supported by an independent randomized small study comparing pegaptanib injections every 6 weeks to pan­ retinal photocoagulation in which more eyes submitted to anti-VEGF therapy responded with complete neovascularization regression.44

RETINAL VEIN OCCLUSION

To study the effect of pegaptanib in another major retinal vascular disease involving ischemic-induced hyperpermeability and neovascularization, a randomized, multicenter, double-masked, sham-con- trolled, phase II trial was conducted with subjects presenting recent vision loss from macular edema secondary to central retinal vein occlusion.45 In the trial, 98 subjects were randomized to receive pegaptanib