Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials.

PURPOSE: To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). DESIGN: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. PARTICIPANTS: Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). METHODS: Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. MAIN OUTCOME MEASURES: Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). RESULTS: At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were -13.88 (1.40) and -7.64 (1.20) in Proxima A, -9.49 (1.29) and -7.57 (1.26) in Proxima B fellow eye CNV cohort, and -11.48 (3.39) and -8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. CONCLUSIONS: The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.

BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.

Intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion.

PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. METHODS: Patients with macular edema secondary to perfused central retinal vein occlusion were enrolled in this ongoing, prospective, open-label study. Treatment was initiated with monthly intravitreal ranibizumab for 3 months. In the first year, additional injections were administered for edema in quarterly intervals as needed (PRN) for Cohort 1 (n = 10) and monthly PRN for Cohort 2 (n = 10). In the second year of treatments, all patients received monthly PRN treatment. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness, fundus photographs, and fluorescein angiograms were evaluated, and the incidence and severity of adverse events were documented. RESULTS: Mean change in best-corrected visual acuity and central retinal thickness improved during the induction phase in both groups. During the remainder of the first year for Cohort 1, initial gains were lost during quarterly treatment but returned with monthly PRN treatment in the second year. For Cohort 2, improvement in best-corrected visual acuity and central retinal thickness from the induction phase was maintained through Month 24. Nineteen of 20 patients experienced a reduction in intraretinal hemorrhage, optic nerve swelling, and/or venous diameter after treatment. One myocardial infarction, one cerebrovascular accident, and no serious ocular adverse events were reported. Iris neovascularization was developed in none of the eyes. CONCLUSION: Ranibizumab was well tolerated and associated with a greater reduction in macular edema and improvement in visual acuity in the monthly PRN regimen compared with quarterly treatment. Vision lost during the quarterly PRN injection intervals in the first year of Cohort 1 could be regained by switching to monthly PRN dosing.

Cystoid macular edema secondary to Paclitaxel (abraxane).

PURPOSE: To report a case of cystoid macular edema secondary to systemic paclitaxel. METHODS: A 58-year-old man with Stage 4 metastatic cutaneous melanoma presented with decreased vision and macular edema while having minimal fluorescein leakage 7 months into a course of paclitaxel chemotherapy. The edema continued to worsen, and vision declined until paclitaxel therapy was discontinued. Six weeks after cessation of paclitaxel, the edema had completely resolved and vision returned to normal. CONCLUSION: Paclitaxel use can result in reversible vision loss associated with angiographically silent macular edema.

Retinal neovascularization associated with a retinal arterial macroaneurysm.

PURPOSE: This case report describes an uncommon presence of a retinal arterial macroaneurysm complicated by retinal neovascularization. METHODS: This is a case history of a 49-year-old woman presenting with preretinal, intraretinal, and subretinal hemorrhage with an adjacent retinal arterial macroaneurysm complicated by the development of retinal neovascularization. RESULTS: The neovascularization, intraretinal lipid, and retinal and preretinal hemorrhage resolved after laser photocoagulation, topical steroids, and nonsteroidal antiinflammatory agent treatment. CONCLUSION: The rapid development of a large frond of neovascularization is atypical for retinal arterial macular aneurysms and has not been previously reported.

Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion.

PURPOSE: To report the authors' experience after intravitreal bevacizumab (Avastin, Genentech) injection in patients with macular edema (ME) secondary to branch retinal vein occlusive disease (BRVO). METHODS: A consecutive retrospective review of patients with ME secondary to BRVO who were treated with intravitreal bevacizumab (1.25 mg/0.05 mL). Patients underwent complete ophthalmic evaluation, which included nonstandardized Snellen visual acuity testing, optical coherence tomography (OCT), and/or angiographic testing at baseline and follow-up visits. RESULTS: There were 27 consecutive patients who received intravitreal bevacizumab injections. The mean length of follow-up was 5.3 months (median 6 months, range 3-8 months). The mean visual acuity improved from 20/200(-) at baseline to 20/100(-) at 1 month and 20/100(+) at 3 months and last follow-up (P < 0.001). The mean central 1 mm macular thickness was 478 microm at baseline and decreased to 310, 336, and 332 microm at 1 month, 3 months, and last follow-up (P < 0.001). Patients received an average of two injections (range one to three). No adverse side effects were observed following injections. CONCLUSION: The observed anatomic (by ophthalmic examination, OCT, and/or fluorescence angiography) and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab injection demonstrates, in principle, the potential of bevacizumab for the treatment of ME in this setting.

Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.

PURPOSE: To report the biologic effect of intravitreal bevacizumab in patients with retinal and iris neovascularization secondary to diabetes mellitus. DESIGN: Interventional, consecutive, retrospective, case series. PARTICIPANTS: Forty-five eyes of 32 patients with retinal and/or iris neovascularization secondary to diabetes mellitus. METHODS: Patients received intravitreal bevacizumab (6.2 microg-1.25 mg). Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography. MAIN OUTCOME MEASURES: Change in fluorescein angiographic leakage of the proliferative diabetic retinopathy (PDR). Secondary outcomes included changes in Snellen VA. RESULTS: No significant ocular or systemic adverse events were observed. All patients with neovascularization demonstrated by fluorescein angiography (44/44 eyes) had complete (or at least partial) reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 19 of 26 (73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 hours after injection. In addition to the reduction in angiographic leakage, the neovascularization clinically appeared to involute in many patients with a reduction in the caliber or presence of perfused blood vessels. In 2 cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied. Recurrent leakage was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at last follow-up of 11 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with a rapid regression of retinal and iris neovascularization secondary to PDR. A consistent biologic effect was noted, even with the lowest dose (6.2 microg) tested, supporting proof of concept. The observation of a possible therapeutic effect in the fellow eye raises concern that systemic side effects are possible in patients undergoing treatment with intravitreal bevacizumab (1.25 mg), and lower doses may achieve a therapeutic result with less risk of systemic side effects. Further study is indicated.

Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

PURPOSE: To report the short-term safety, biologic effect, and a possible mechanism of action of intravitreal bevacizumab in patients with neovascular age-related macular degeneration (AMD). DESIGN: Interventional, consecutive, retrospective case series. PARTICIPANTS: Eighty-one eyes of 79 patients with subfoveal neovascular AMD. METHODS: Patients received intravitreal bevacizumab (1.25 mg) on a monthly basis until macular edema, subretinal fluid (SRF), and/or pigment epithelial detachment (PED) resolved. Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography (OCT). MAIN OUTCOME MEASURES: Assessments of safety, changes in Snellen VA, OCT retinal thickness, and angiographic lesion characteristics were performed. RESULTS: No significant ocular or systemic side effects were observed. Most patients (55%) had a reduction of >10% of baseline retinal thickness at 1 week after the injection. At 4 weeks after injection, 30 of 81 eyes demonstrated complete resolution of retinal edema, SRF, and PEDs. Of the 51 eyes with 8 weeks' follow-up, 25 had complete resolution of retinal thickening, SRF, and PEDs. At 1, 4, 8,and 12 weeks, the mean retinal thickness of the central 1 mm was decreased by 61, 92, 89, and 67 mum, respectively (P<0.0001 for 1, 4, and 8 weeks and P<0.01 for 12 weeks). At 4 and 8 weeks, mean VA improved from 20/200 to 20/125 (P<0.0001). Median vision improved from 20/200 to 20/80(-) at 4 weeks and from 20/200 to 20/80 at 8 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab (1.25 mg) is well tolerated and associated with improvement in VA, decreased retinal thickness by OCT, and reduction in angiographic leakage in most patients, the majority of whom had previous treatment with photodynamic therapy and/or pegaptanib. Further evaluation of intravitreal bevacizumab for the treatment of choroidal neovascularization is warranted.