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Abstract: The role of vascular endothelial growth factor (VEGF), including in retinal vascular diseases, has been well studied, and pharmacological blockade of VEGF is the gold standard of treatment for neovascular age‐related macular degeneration, retinal vein occlusion and diabetic macular oedema. Placental growth factor (PGF, previously known as PlGF), a homologue of VEGF, is a multifunctional peptide associated with angiogenesis‐dependent pathologies in the eye and non‐ocular conditions. Animal studies using genetic modification and pharmacological treatment have demonstrated a mechanistic role for PGF in pathological angiogenesis. Inhibition decreases neovascularization and microvascular abnormalities across different models, including oxygen‐induced retinopathy, laser‐induced choroidal neovascularization and in diabetic mice exhibiting retinopathies. High levels of PGF have been found in the vitreous of patients with diabetic retinopathy. Despite these strong animal data, the exact role of PGF in pathological angiogenesis in retinal vascular diseases remains to be defined, and the benefits of PGF‐specific inhibition in humans with retinal neovascular diseases and macular oedema remain controversial. Comparative effectiveness research studies in patients with diabetic retinal disease have shown that treatment that inhibits both VEGF and PGF may provide superior outcomes in certain patients compared with treatment that inhibits only VEGF. This review summarizes current knowledge of PGF, including its relationship to VEGF and its role in pathological angiogenesis in retinal diseases, and identifies some key unanswered questions about PGF that can serve as a pathway for future basic, translational and clinical research. [ABSTRACT FROM AUTHOR]

Purpose To evaluate visual and anatomic outcomes after intravitreal aflibercept injection (IAI) versus laser in diabetic macular edema (DME) patients with and without prior anti–vascular endothelial growth factor (VEGF) treatment for DME. Design Post hoc analysis of eyes from 2 similarly designed, phase 3 trials, VISTA and VIVID. Participants Patients (eyes) with DME with central involvement from VISTA (n = 461) and VIVID (n = 404). Methods Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation. Main Outcome Measures This study reports exploratory outcomes through week 100. Analyses focused on VISTA because more patients received prior anti-VEGF therapy in VISTA (42.9%) versus VIVID (8.9%). Results Of 42.9% of patients in VISTA who received prior anti-VEGF treatment, 83.3% to 92.6% received ≥ 1 prior injections of bevacizumab, and 71.4% to 82.4% received bevacizumab only as prior anti-VEGF treatment for a duration ranging from 28 days to 3.9 years. In patients with prior anti-VEGF treatment, mean best-corrected visual acuity (BCVA) changes from baseline in the IAI 2q4, IAI 2q8, and laser groups were +10.4 letters, +10.5 letters, and −0.7 letters at week 52 and +10.9 letters, +10.8 letters, and −0.8 letters at week 100, respectively. Corresponding changes in patients without prior anti-VEGF treatment were +14.1 letters, +11.0 letters, and +0.9 letters at week 52 and +12.0 letters, +11.3 letters, and +2.1 letters at week 100. In patients with prior anti-VEGF treatment, mean reductions in central retinal thickness were 180.2 μm, 192.2 μm, and 90.9 μm at week 52 and 180.1 μm, 196.4 μm, and 94.1 μm at week 100. Corresponding reductions in patients without prior anti-VEGF treatment were 190.3 μm, 175.7 μm, and 61.0 μm at week 52 and 200.0 μm, 186.7 μm, and 76.9 μm at week 100. The most frequent serious ocular adverse event was vitreous hemorrhage (1.3%, 0.7%, and 1.9%, respectively). Conclusions Visual and anatomic improvements over laser with both IAI regimens were significant and similar through week 100 in subgroups of patients in VISTA with and without prior anti-VEGF treatment for DME. [ABSTRACT FROM AUTHOR]

Purpose: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). Methods: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. Results: Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 ( P=0.0065), 23.8 versus 5.9 at week 6 ( P=0.0380), and 25.2% versus 11.3% at week 8 ( P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. Conclusions: Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients. [ABSTRACT FROM AUTHOR]

Purpose: To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME). Design: Randomized, double-masked, multicenter, phase 2 clinical trial. Participants: Diabetic patients (n = 221) with center-involved DME. Methods: Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation. Main Outcome Measures: The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline. Results: As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (P ≤ 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus −1.3 letters for the laser group (P ≤ 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser (P = 0.0031, P = 0.0007, P = 0.1608, and P = 0.0016, respectively, versus laser). Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were −165.4 μm, −227.4 μm, −187.8 μm, and −180.3 μm versus −58.4 μm for laser (P < 0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated. The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure. Conclusions: Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation for the treatment of DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Purpose: To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients. Design: Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection–controlled, randomized studies. Participants: Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40–20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT). Intervention: Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol–specified criteria. Main Outcome Measures: Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months. Results: In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8–34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7–31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4–30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8–42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3–0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients. Conclusions: Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Purpose: The role of vascular endothelial growth factor (VEGF) in diabetic macular edema (DME) was tested with ranibizumab, a specific antagonist of VEGF. Design: A nonrandomized clinical trial. Methods: Ten patients with chronic DME received intraocular injections of 0.5 mg of ranibizumab at baseline and at one, two, four, and six months. The primary outcome was change in foveal thickness between baseline and seven months, and the secondary outcome measures were changes from baseline in visual acuity and macular volume. Results: Mean values at baseline were 503 μm for foveal thickness, 9.22 mm3 for macular volume, and 28.1 letters (20/80) read on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. At seven months (one month after the fifth injection), the mean foveal thickness was 257 μm, which was a reduction of 246 μm (85% of the excess foveal thickness present at baseline; P = .005 by Wilcoxon signed-rank test for likelihood that this change is due to ranibizumab rather than chance). The macular volume was 7.47 mm3, which was a reduction of 1.75 mm3 (77% of the excess macular volume at baseline; P = .009). Mean visual acuity was 40.4 letters (20/40), which was an improvement of 12.3 letters (P = .005). The injections were well-tolerated with no ocular or systemic adverse events. Conclusion: Intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in 10 patients with DME, which demonstrated that VEGF is an important therapeutic target for DME. A randomized, controlled, double-masked trial is needed to test whether intraocular injections of ranibizumab provide long-term benefit to patients with DME. [Copyright &y& Elsevier]

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars. • Biologics against VEGF are crucial for the treatment of many retinal diseases. • Ophthalmic anti-VEGF reference biologics typically impose high financial burden. • Approved anti-VEGF biosimilars are clinically equivalent to reference products. • Biosimilars can bring substantial benefits to patients and healthcare systems by reducing cost. • Realization of biosimilar benefits depend, in part, on their successful uptake. [ABSTRACT FROM AUTHOR]

The following are highlights from a case discussion, which was moderated by the Course Director, Quan Dong Nguyen, MD, MSc. The faculty reviewed 3 case studies and discussed their different approaches to managing the treatment of each patient. They also fielded questions from audience members about their management suggestions and the potential US Food and Drug Administration approval of aflibercept, which was not approved at the time of this discussion. In addition, the 2-year CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) results and 1-year IVAN (Inhibit Vascular Endothelial Growth Factor in Age-Related Choroidal Neovascularization) results were not released at the time this discussion took place. [Copyright &y& Elsevier]

Objective: To evaluate anatomic outcomes and vision, injection frequency, and safety during the as-needed (PRN) treatment phase of a study evaluating a 12-week fixed dosing period followed by PRN dosing to week 52 with vascular endothelial growth factor (VEGF) Trap-Eye for neovascular (wet) age-related macular degeneration (AMD). Design: Multicenter, randomized, double-masked trial. Participants: We included 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet AMD. Methods: Patients were randomly assigned to 1 of 5 intravitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1–12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). Main Outcome Measures: Change in central retinal/lesion thickness (CR/LT), change in total lesion and CNV size, mean change in best-corrected visual acuity (BCVA), proportion of patients with 15-letter loss or gain, time to first PRN injection, reinjection frequency, and safety at week 52. Results: The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (−130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm2 at 48 weeks. After achieving a significant improvement in BCVA during the 12-week, fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; P<0.0001). The most robust improvements and consistent maintenance of visual acuity generally occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first reinjection was 129 days; 19% of patients received no injections and 45% received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well tolerated, with few ocular or systemic adverse events. Conclusions: PRN dosing with VEGF Trap-Eye at weeks 16-52 maintained the significant anatomic and vision improvements established during the 12-week fixed-dosing phase with a low frequency of reinjections. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

The article discusses anti-vascular endothelial growth factor (VEGF) agents for managing diabetic macular edema (DME). It elaborates on the mechanism of action and efficacy of anti-VEGF agents such as Pegaptanib, Ranibizumab, Bevacizumab, VEGF Trap, Bevasiranib, and Rapamycin. The author concludes that the whole gamut of anti-VEGF agents, including the ophthalmological milestone of ocular anti-VEGF therapy development, offers clinicians a better option to manage DME.

Purpose A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). Design Two similarly designed, double-masked, randomized, phase 3 trials, VISTA DME and VIVID DME . Participants We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. Methods Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. Main Outcome Measures The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. Results Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters ( P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters ( P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥15 letters were 41.6% and 31.1% versus 7.8% ( P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% ( P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 μm ( P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 μm ( P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration–defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. Conclusions At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the biologic effects and safety of vascular endothelial growth factor (VEGF) Trap-Eye during a 12-week fixed-dosing period in patients with neovascular (wet) age-related macular degeneration (AMD). Design: Multicenter, prospective, randomized, double-masked clinical trial with initial 12-week fixed dosing period. Data were analyzed to week 16. Participants: We included 159 patients with subfoveal choroidal neovascularization secondary to wet AMD. Methods: Patients were randomized 1:1:1:1:1 to VEGF Trap-Eye during the fixed-dosing phase (day 1 to week 12): 0.5 or 2 mg every 4 weeks (0.5 mg q4wk, 2 mg q4wk) on day 1 and at weeks 4, 8, and 12; or 0.5, 2, or 4 mg every 12 weeks (0.5 mg q12wk, 2 mg q12wk, or 4 mg q12wk) on day 1 and at week 12. Main Outcome Measures: The primary endpoint was change from baseline in central retinal/lesion thickness (CR/LT) at week 12; secondary outcomes included change in best-corrected visual acuity (BCVA), proportion of patients with a gain of ≥15 letters, proportion of patients with a loss of >15 letters, and safety. Results: At week 12, treatment with VEGF Trap-Eye resulted in a significant mean decrease in CR/LT of 119 μm from baseline in all groups combined (P<0.0001). The reduction in CR/LT with the 2 mg q4wk and 0.5mg q4wk regimens was significantly greater than each of the quarterly dosing regimens. The BCVA increased significantly by a mean of 5.7 letters at 12 weeks in the combined group (P<0.0001), with the greatest mean gain of >8 letters in the monthly dosing groups. At 8 weeks, BCVA improvements were similar with 2 mg q4wk and 2 mg q12wk dosing. After the last required dose at week 12, CR/LT and visual acuity were maintained or further improved at week 16 in all treatment groups. Ocular adverse events were mild and consistent with safety profiles reported for other intraocular anti-VEGF treatments. Conclusions: Repeated monthly intravitreal dosing of VEGF Trap-Eye over 12 weeks demonstrated significant reductions in retinal thickness and improvements in visual acuity, and was well-tolerated in patients with neovascular AMD. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Purpose: To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor (VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs). Design: Prospective randomized trial. Participants: Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with central RVOs (CRVOs). Methods: After the month 3 primary end point, patients were seen every 2 months and received injections of an anti-VEGF agent as needed for recurrent edema. Main Outcome Measures: Mean change from baseline best-corrected visual acuity (BCVA) at month 24 with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]). Results: For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH at month 24 was 245.8 μm compared with 217.1 μm at month 3 and 481.5 μm at baseline. For 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 μm compared with 278 μm at month 3 and 533 μm at baseline. Duration of RVO >1 year at study entry and nonperfusion of perifoveal capillaries for 360 degrees correlated with reduced visual outcomes. Conclusions: Antagonism of VEGF provides substantial long-term benefit to patients with macular edema caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Purpose: To assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). Secondary objectives included assessment of anatomic changes in retinal thickness, size of CNV, and changes in visual acuity. Design: Prospective, open-label, single-dose, dose-escalation phase 1 study. Methods: Twenty-six eyes of 26 patients with a median age of 82 years and CNV resulting from AMD who had previous treatments with other therapies were treated at 2 academic retinal practices. Patients received a single dose of Sirna-027 (100, 200, 400, 800, 1200, or 1600 μg/eye). Blood was sampled for pharmacokinetic analysis at 1, 4, and 24 hours after injection and on day 7. Patients underwent ophthalmic examinations including visual acuity, fluorescein angiography, and optical coherence tomography at screening and days 7, 14, 28, and 84. The main outcome measures were adverse reactions and dose-limiting toxicities. Results: Intravitreal injection of a single dose of Sirna-027 from 100 to 1600 μg was well tolerated in patients with AMD, with no dose-limiting toxicity found. Adverse events were mild to moderate in severity. Adjusted mean foveal thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100- and 200-μg doses. Conclusions: A single intravitreal dose of Sirna-027 up to 1600 μg/eye was well tolerated in patients with CNV resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted. [Copyright &y& Elsevier]