Macular Degeneration: Cunningham ET

Shukla D, Namperumalsamy P, Goldbaum M, Cunningham ET. · Retina-Vitreous Service, Aravind Eye Hospital and Postgraduate Institute, Anna Nagar, Madurai, India. · Indian J Ophthalmol. · Pubmed #17951898 links to  free full text

Abstract: Pegaptanib sodium (Macugen) is a selective RNA aptamer that inhibits vascular endothelial growth factor (VEGF) 165 , the VEGF isoform primarily responsible for pathologic ocular neovascularization and vascular permeability, while sparing the physiological isoform VEGF 121 . After more than 10 years in development and preclinical study, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Its excellent ocular and systemic safety profile has also been confirmed in patients receiving up to three years of therapy. Early, well-controlled studies further suggest that pegaptanib may provide therapeutic benefit for patients with diabetic macular edema, proliferative diabetic retinopathy and retinal vein occlusion. Notably, pegaptanib was the first available aptamer approved for therapeutic use in humans and the first VEGF inhibitor available for the treatment of ocular vascular diseases.

Ng EW, Shima DT, Calias P, Cunningham ET, Guyer DR, Adamis AP. · Eyetech Pharmaceuticals, Inc., 3 Times Square, 12th Floor, New York, New York 10036, USA. · Nat Rev Drug Discov. · Pubmed #16518379 No free full text.

Abstract: Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability. After nearly a decade of preclinical development to optimize and characterize its biological effects, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.

Wroblewski JJ, Wells JA, Adamis AP, Buggage RR, Cunningham ET, Goldbaum M, Guyer DR, Katz B, Altaweel MM, Anonymous00045. · Cumberland Valley Retina Consultants, Hagerstown, Maryland 21740, USA. · Arch Ophthalmol. · Pubmed #19365011 No free full text.

Abstract: OBJECTIVES: To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO). DESIGN: This dose-ranging, double-masked, multicenter, phase 2 trial included subjects with CRVO for 6 months' or less duration randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32). MAIN OUTCOME MEASURE: Visual acuity at week 30. RESULTS: In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 (28%) sham-treated subjects (P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs -3.2 letters with sham; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm, respectively, vs 5 microm with sham (P< .001). CONCLUSIONS: Based on this 30-week study, intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO. APPLICATION TO CLINICAL PRACTICE: Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088283.

Cunningham ET, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D'Amico DJ, Goldbaum M, Guyer DR, Katz B, Patel M, Schwartz SD, Anonymous00243. · Stanford University, USA. · Ophthalmology. · Pubmed #16154196 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS: Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION: Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES: Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS: One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS: In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.

Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR, Anonymous00336. · Retina Service, Massachusetts Eye and Ear Infirmary and Harvard Medical School, 243 Charles St., Boston, MA 02114, USA. · N Engl J Med. · Pubmed #15625332 links to  free full text

Abstract: BACKGROUND: Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration. METHODS: We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks. RESULTS: In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Among the adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic injury to the lens (in 0.7 percent), and retinal detachment (in 0.6 percent) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1 percent of patients. CONCLUSIONS: Pegaptanib appears to be an effective therapy for neovascular age-related macular degeneration. Its long-term safety is not known.

Anonymous00326, Chakravarthy U, Adamis AP, Cunningham ET, Goldbaum M, Guyer DR, Katz B, Patel M. · Centre for Vision Sciences, The Queen's University of Belfast and The Royal Victoria Hospital, Belfast, United Kingdom. · Ophthalmology. · Pubmed #16828500 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of a second year of pegaptanib sodium therapy in patients with neovascular age-related macular degeneration (AMD). DESIGN: Two concurrent, multicenter, randomized, double-masked, sham-controlled studies (V.I.S.I.O.N. [Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization] trials). PARTICIPANTS: Patients with all angiographic neovascular lesion compositions of AMD were enrolled. In combined analyses, 88% (1053/1190) were re-randomized at week 54, and 89% (941/1053) were assessed at week 102. INTERVENTIONS: At week 54, those initially assigned to pegaptanib were re-randomized (1:1) to continue or discontinue therapy for 48 more weeks (8 injections). Those initially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. MAIN OUTCOME MEASURES: Mean change in visual acuity (VA) over time and mean change in the standardized area under the curve of VA and proportions of patients experiencing a loss of > or =15 letters from week 54 to week 102; losing <15 letters (responders) from baseline to week 102; gaining > or =0, > or =1, > or =2, and > or =3 lines of VA; and progressing to legal blindness (20/200 or worse). RESULTS: In combined analysis, mean VA was maintained in patients continuing with 0.3-mg pegaptanib compared with those discontinuing therapy or receiving usual care. In patients who continued pegaptanib, the proportion who lost >15 letters from baseline in the period from week 54 to week 102 was half (7%) that of patients who discontinued pegaptanib or remained on usual care (14% for each). Kaplan-Meier analysis showed that patients continuing 0.3-mg pegaptanib for a second year were less likely to lose > or =15 letters than those re-randomized to discontinue after 1 year (P<0.05). The proportion of patients gaining vision was higher for those assigned to 2 years of 0.3-mg pegaptanib than receiving usual care. Progression to legal blindness was reduced for patients continuing 0.3-mg pegaptanib for 2 years. CONCLUSIONS: Continuing visual benefit was observed in patients who were randomized to receive therapy with pegaptanib in year 2 of the V.I.S.I.O.N. trials when compared with 2 years' usual care or cessation of therapy at year 1.

Anonymous00201, D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET, Guyer DR, Katz B. · Department of Ophthalmology, Harvard Medical School, Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. · Ophthalmology. · Pubmed #16647134 No free full text.

Abstract: OBJECTIVE: To evaluate the safety of pegaptanib sodium injection, a specific vascular endothelial growth factor (VEGF) antagonist, in the treatment of neovascular age-related macular degeneration (AMD) during 2 years of therapy. DESIGN: Two concurrent, prospective, randomized, multicenter, double-masked, sham-controlled studies. METHODS: Patients with all angiographic choroidal neovascularization lesion compositions of AMD received either intravitreous pegaptanib sodium (0.3 mg, 1 mg, 3 mg) or sham injections every 6 weeks for 54 weeks. Those initially assigned to pegaptanib were re-randomized (1:1) to continue or discontinue therapy for 48 more weeks; sham-treated patients were re-randomized (1:1:1:1:1) to continue sham, discontinue, or receive one of the pegaptanib doses. MAIN OUTCOME MEASURES: All reported adverse events, serious adverse events, and deaths. PARTICIPANTS: In year 1, 1190 subjects received at least one study treatment (0.3 mg, n = 295; 1 mg, n = 301; 3 mg, n = 296; sham, n = 298); 7545 intravitreous injections of pegaptanib were administered. In year 2, 425 subjects (0.3 mg, n = 128; 1 mg, n = 126; 3 mg, n = 120; sham, n = 51) continued the same masked treatment as in year 1 and received at least one study treatment in year 2; 2663 intravitreous injections of pegaptanib were administered in these subjects. RESULTS: All doses of pegaptanib were well tolerated. The most common ocular adverse events were transient, mild to moderate in intensity, and attributed to the injection preparation and procedure. There was no evidence of an increase in deaths, in events associated with systemic VEGF inhibition (e.g., hypertension, thromboembolic events, serious hemorrhagic events), or in severe ocular inflammation, cataract progression, or glaucoma in pegaptanib-treated patients relative to sham-treated patients. In year 1, serious injection-related complications included endophthalmitis (12 events, 0.16%/injection), retinal detachment (RD) (6 events [4 rhegmatogenous, 2 exudative], 0.08%/injection), and traumatic cataract (5 events, 0.07%/injection). Most cases of endophthalmitis followed violations of the injection preparation protocol. In patients receiving pegaptanib for >1 year, there were no reports of endophthalmitis or traumatic cataract in year 2; RD was reported in 4 patients (all rhegmatogenous, 0.15%/injection). CONCLUSION: The 2-year safety profile of pegaptanib sodium is favorable in patients with exudative AMD.

Adamis AP, Altaweel M, Bressler NM, Cunningham ET, Davis MD, Goldbaum M, Gonzales C, Guyer DR, Barrett K, Patel M, Anonymous00106. · No affiliation provided · Ophthalmology. · Pubmed #16343627 No free full text.

Abstract: OBJECTIVE: To study effects of intravitreal pegaptanib (Macugen) on retinal neovascularization. DESIGN: Retrospective analysis of a randomized clinical trial. PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURES: Individuals with retinal neovascularization identified from a multicenter, randomized, controlled trial evaluating pegaptanib for treatment of diabetic macular edema, with a best-corrected visual acuity letter score between 68 and 25 (approximate Snellen equivalent between 20/50 and 20/320) and receiving a sham injection or intravitreal pegaptanib (0.3 mg, 1 mg, 3 mg) administered at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed during the ensuing 18 weeks, up to a maximum of 6 pegaptanib/sham therapies, were evaluated. Scatter panretinal photocoagulation before study enrollment was permitted, but not within 6 months of randomization and study entry. Changes in retinal neovascularization were assessed on fundus photographs and fluorescein angiograms graded at a reading center in a masked fashion. RESULTS: Of 172 participants, 19 had retinal neovascularization in the study eye at baseline. Excluding 1 who had scatter photocoagulation 13 days before randomization and 2 with no follow-up photographs, 1 of the remaining 16 subjects had panretinal photocoagulation during study follow-up. Of these 16 subjects, 8 of 13 (62%) in a pegaptanib treatment group (including the one receiving panretinal photocoagulation), 0 of 3 in the sham group, and 0 of 4 fellow (nonstudy) eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30. CONCLUSIONS: Most subjects with retinal neovascularization at baseline assigned to pegaptanib showed regression of neovascularization by week 36. These findings suggest a direct effect of pegaptanib upon retinal neovascularization in patients with diabetes mellitus.

Stewart JM, Cubillan LD, Cunningham ET. · Francis I. Proctor Foundation and the Department of Ophthalmology, University of California at San Francisco, San Francisco, California, USA. · Retina. · Pubmed #16340531 No free full text.

Abstract: BACKGROUND: To describe the prevalence, clinical features, and causes of vision loss among patients with ocular toxocariasis seen at a uveitis referral center. METHODS: A review was completed of the charts of patients with ocular toxocariasis who were examined between 1977 and 1996 at the Francis I. Proctor Foundation of the University of California at San Francisco. The prevalence of ocular toxocariasis among all uveitis patients seen at the center was determined. Demographic features, symptoms, and signs in all patients were evaluated. RESULTS: Ocular toxocariasis occurred in 22 (1.0%) of 2,185 uveitis patients. The mean patient age was 16.5 years. Inflammation was usually unilateral (90.9%). Toxocara uveitis presented as a granuloma in the peripheral retina in 50% of cases, as a granuloma in the macula in 25% of cases, and as a moderate to severe vitreous inflammation mimicking endophthalmitis in 25% cases. The primary causes of vision loss were vitritis (52.6%), cystoid macular edema (47.4%), and traction retinal detachment (36.8%). CONCLUSIONS: Ocular toxocariasis is an uncommon cause of uveitis that mainly affects younger patients. Inflammation is typically unilateral and presents as either a granuloma in the peripheral or posterior retina or a moderate to severe vitreous inflammation mimicking endophthalmitis.