Brolucizumab Versus Aflibercept in Participants with Neovascular Age-Related Macular Degeneration: A Randomized Trial.

PURPOSE: To compare the efficacy and safety of brolucizumab with aflibercept to treat neovascular age-related macular degeneration (AMD). DESIGN: Prospective, randomized, double-masked, multicenter, 2-arm, phase 2 study. PARTICIPANTS: Eighty-nine treatment-naïve participants, aged ≥50 years, with active choroidal neovascularization secondary to AMD. METHODS: Eligible participants were randomized 1:1 to intravitreal brolucizumab (6 mg/50 µl) or aflibercept (2 mg/50 µl). Both groups received 3 monthly loading doses and were then treated every 8 weeks (q8) with assessment up to week 40. In the brolucizumab group, the final q8 cycle was extended to enable 2 cycles of treatment every 12 weeks (q12; to week 56); participants on aflibercept continued on q8. Unscheduled treatments were allowed at the investigator's discretion. MAIN OUTCOME MEASURES: The primary and secondary hypotheses were noninferiority (margin: 5 letters at a 1-sided alpha level 0.1) in best-corrected visual acuity (BCVA) change from baseline of brolucizumab versus aflibercept at weeks 12 and 16, respectively. BCVA, central subfield thickness (CSFT), and morphologic features were assessed throughout the study. RESULTS: The mean BCVA change from baseline (letters) with brolucizumab was noninferior to aflibercept at week 12 (5.75 and 6.89, respectively [80% confidence interval for treatment difference, -4.19 to 1.93]) and week 16 (6.04 and 6.62 [-3.72 to 2.56]), with no notable differences up to week 40. Outcomes exploring disease activity during the q8 treatment cycles suggest greater stability of the brolucizumab participants, supported by receipt of fewer unscheduled treatments versus aflibercept (6 vs. 15) and more stable CSFT reductions. In addition, from post hoc analysis, a greater proportion of brolucizumab-treated eyes had resolved intraretinal and subretinal fluid compared with aflibercept-treated eyes. Approximately 50% of brolucizumab-treated eyes had stable BCVA during the q12 cycles. Brolucizumab and aflibercept adverse events were comparable. CONCLUSIONS: During the matched q8 phase, the BCVA in brolucizumab-treated eyes appeared comparable to aflibercept-treated eyes, with more stable CSFT reductions, receipt of fewer unscheduled treatments, and higher rates of fluid resolution. The brolucizumab safety profile was similar to aflibercept over 56 weeks of treatment. A 12-week treatment cycle for brolucizumab may be viable in a relevant proportion of eyes.

Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration.

BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 µM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of fenretinide in chronic dosing regimens warrant further study of fenretinide in the treatment of geographic atrophy.

Detection of new-onset choroidal neovascularization using optical coherence tomography: the AMD DOC Study.

PURPOSE: To determine the sensitivity of time domain optical coherence tomography (OCT) in detecting conversion to neovascular age-related macular degeneration (AMD) in eyes at high risk for choroidal neovascularization (CNV), compared with detection using fluorescein angiography (FA) as the gold standard. DESIGN: Prospective, multicenter, observational study. PARTICIPANTS: Individuals aged ≥50 years with nonneovascular AMD at high risk of progressing to CNV in the study eye and evidence of neovascular AMD in the fellow eye. METHODS: At study entry and every 3 months through 2 years, participants underwent best-corrected visual acuity, supervised Amsler grid testing, preferential hyperacuity perimetry (PHP) testing, stereoscopic digital fundus photographs with FA, and OCT imaging. A central Reading Center graded all images. MAIN OUTCOMES MEASURES: The sensitivity of OCT in detecting conversion to neovascular AMD by 2 years, using FA as the reference standard. Secondary outcomes included comparison of sensitivity, specificity, positive predictive value, and negative predictive value of OCT, PHP, and supervised Amsler grid relative to FA for detecting incident CNV. RESULTS: A total of 98 participants were enrolled; 87 (89%) of these individuals either completed the 24-month visit or exited the study after developing CNV. Fifteen (17%) study eyes had incident CNV confirmed on FA by the Reading Center. The sensitivity of each modality for detecting CNV was: OCT 0.40 (95% confidence interval [CI], 0.16-0.68), supervised Amsler grid 0.42 (95% CI, 0.15-0.72), and PHP 0.50 (95% CI, 0.23-0.77). Treatment for incident CNV was recommended by the study investigator in 13 study eyes. Sensitivity of the testing modalities for detection of CNV in these 13 eyes was 0.69 (95% CI, 0.39-0.91) for OCT, 0.50 (95% CI, 0.19-0.81) for supervised Amsler grid, and 0.70 (95% CI, 0.35-0.93) for PHP. Specificity of the OCT was higher than that of the Amsler grid and PHP. CONCLUSIONS: Time-domain OCT, supervised Amsler grid, and PHP have low to moderate sensitivity for detection of new-onset CNV compared with FA. Optical coherence tomography has greater specificity than Amsler grid or PHP. Among fellow eyes of individuals with unilateral CNV, FA remains the best method to detect new-onset CNV.

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.

OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO). METHODS: Multicenter, randomized, clinical trial of 271 participants. MAIN OUTCOME MEASURE: Gain in visual acuity letter score of 15 or more from baseline to month 12. RESULTS: Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group. CONCLUSIONS: Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial. Trial Registration clinicaltrials.gov Identifier: NCT00105027.

A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6.

OBJECTIVE: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: Multicenter, randomized clinical trial of 411 participants. Main Outcome Measure Gain in visual acuity letter score of 15 or more from baseline to month 12. RESULTS: Twenty-nine percent, 26%, and 27% of participants achieved the primary outcome in the standard care, 1-mg, and 4-mg groups, respectively. None of the pairwise comparisons between the 3 groups was statistically significant at month 12. The rates of elevated intraocular pressure and cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group. CONCLUSIONS: There was no difference identified in visual acuity at 12 months for the standard care group compared with the triamcinolone groups; however, rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group. Application to Clinical Practice Grid photocoagulation as applied in the SCORE Study remains the standard care for patients with vision loss associated with macular edema secondary to BRVO who have characteristics similar to participants in the SCORE-BRVO trial. Grid photocoagulation should remain the benchmark against which other treatments are compared in clinical trials for eyes with vision loss associated with macular edema secondary to BRVO. Trial Registration clinicaltrials.gov Identifier: NCT00105027.

Combination therapy using the small interfering RNA bevasiranib.

Bevasiranib, the first small interfering RNA agent developed for the treatment of neovascular age-related macular degeneration, has demonstrated clinical promise. Injected intravitreally, this small interfering RNA acts by inducing catalytic destruction of messenger RNA to silence gene expression. Bevasiranib targets the production of vascular endothelial growth factor (VEGF) protein. It does not affect existing VEGF protein, suggesting that it may offer a synergistic effect when given in combination with anti-VEGF treatments, such as ranibizumab. The safety of bevasiranib has been supported by preclinical and clinical research.

Implantable telescope for end-stage age-related macular degeneration: long-term visual acuity and safety outcomes.

PURPOSE: To evaluate long-term safety and best-corrected visual acuity (BCVA) results of a telescope prosthesis in patients with end-stage age-related macular degeneration (AMD). DESIGN: Prospective, open-label clinical trial with fellow-eye controls. METHODS: Patients with end-stage AMD (bilateral geographic atrophy or disciform scars; BCVA, 20/80 to 20/800) received the telescope prosthesis at 28 centers. Methods were similar to those described in the one-year results, with follow-up visits continuing at 18 and 24 months. Main outcome measures included BCVA change from baseline, endothelial cell density (ECD) and morphometry, and incidence of complications. RESULTS: At two years, data from 174 (92.6%) of 188 available patients were analyzed. Overall, 103 (59.5%) of 173 telescope-implanted eyes gained three lines or more (doubling of visual angle) of BCVA compared with 18 (10.3%) of 174 fellow control eyes (P < .0001). Mean BCVA improved 3.6 lines (standard deviation [SD], 1.9 lines) and 2.8 lines (SD, 2.3 lines) from baseline in eyes with the 3X and 2.2X device models, respectively. Mean ECD stabilized through two years, with 2.4% mean cell loss occurring from one to two years. There was no significant change in coefficient of variation or percentage of hexagonal endothelial cells from within six months to two years after surgery. The most common complication was inflammatory deposits. CONCLUSIONS: Long-term results of this telescope prosthesis show the substantial BCVA improvement at one year is maintained at two years. Key indicators of corneal health demonstrate ECD change that reflects remodeling of the endothelium associated with the implantation procedure. ECD stabilizes over time, and there is no evidence of any ongoing endothelial trauma.

A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.

OBJECTIVE: To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME). DESIGN: Randomized phase II clinical trial. PARTICIPANTS: One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320. INTERVENTIONS: Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22). MAIN OUTCOME MEASURES: Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks. RESULTS: At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3). CONCLUSION: These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.

Implantable miniature telescope for the treatment of visual acuity loss resulting from end-stage age-related macular degeneration: 1-year results.

PURPOSE: To evaluate the safety and efficacy of an implantable visual prosthetic device (IMT; VisionCare Ophthalmic Technologies, Saratoga, CA) in patients with bilateral, end-stage age-related macular degeneration (AMD). DESIGN: Prospective, open-label, multicenter clinical trial with fellow eye controls. PARTICIPANTS: A total of 217 patients (mean age, 76 years) with AMD and moderate to profound bilateral central visual acuity loss (20/80-20/800) resulting from bilateral untreatable geographic atrophy, disciform scars, or both were enrolled. METHODS: A visual prosthetic device (implantable telescope), designed to enlarge retinal images of the central visual field, was implanted monocularly in the capsular bag after lens extraction. Fellow eyes were not implanted to provide peripheral vision and served as controls. Study patients participated in 6 visual rehabilitation visits after surgery. MAIN OUTCOME MEASURES: Best-corrected distance visual acuity (BCDVA) and best-corrected near visual acuity (BCNVA), quality-of-life scores from the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) and the Activities of Daily Life scale, endothelial cell density (ECD), and incidence of complications and adverse events. RESULTS: At 1 year, 67% of implanted eyes achieved a 3-line or more improvement in BCDVA versus 13% of fellow eye controls (P<0.0001). Fifty-three percent of implanted eyes achieved a 3-line or more improvement in both BCDVA and BCNVA versus 10% of fellow eyes (P<0.0001). Mean BCDVA and BCNVA improved 3.5 lines and 3.2 lines, respectively, in implanted eyes versus 0.8 lines and 1.8 lines, respectively, in fellow eyes (P<0.0001). Change in visual acuity was not related to lesion type. Mean NEI VFQ-25 scores improved by more than 7 points from baseline (P<0.01) on 7 of 8 relevant subscales. Eleven eyes did not receive the device because of an aborted procedure. Endothelial cell density was reduced by 20% at 3 months and 25% at 1 year. The decrease in ECD was correlated with postsurgical edema (P<0.0001), and there was no evidence that endothelial cell loss is accelerated by ongoing endothelial trauma after implantation. CONCLUSIONS: This implantable visual prosthesis can improve visual acuity and quality of life in patients with moderate to profound visual impairment caused by bilateral, end-stage AMD.

Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes.

PURPOSE: To evaluate safety and efficacy of the angiostatic agent anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV). DESIGN: Ongoing masked, randomized, placebo-controlled, parallel evaluation of anecortave acetate (30 mg, 15 mg, and 3 mg) versus a placebo. PARTICIPANTS: There were 128 eyes of 128 patients with subfoveal CNV secondary to age-related macular degeneration who were enrolled and treated, with 80% (102/128) of eyes presenting with predominantly classic lesions at baseline. METHODS: All eyes received a posterior juxtascleral depot application of masked study medication or a placebo, with retreatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. All ophthalmic and systemic safety data were periodically reviewed by the Independent Safety Committee overseeing the study. MAIN OUTCOME MEASURES: Best-corrected logarithm of the minimum angle of resolution (logMAR) vision and fluorescein angiographic lesion characteristics were compared over time and among treatment groups. RESULTS: At month 12, anecortave acetate (15 mg) administered at 6-month intervals was statistically superior to the placebo for 3 measures of clinical efficacy: mean change from baseline vision (P = 0.0131), stabilization of vision (<3 logMAR line change; P = 0.0323), and prevention of severe vision loss (decrease of > or = 6 logMAR lines from baseline; P = 0.0224). Subgroup analysis of predominantly classic lesions revealed that anecortave acetate (15 mg) was also superior to the placebo at 1 year for each of these 3 measures of visual outcome (Ps = 0.0022, 0.0100, and 0.0299, respectively). Anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses. The Independent Safety Committee identified no clinically relevant treatment-related safety issues. CONCLUSIONS: Anecortave acetate (15 mg) is safe and clinically efficacious at 1 year for maintaining vision, preventing severe vision loss, and inhibiting subfoveal CNV lesion growth.

Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy.

PURPOSE: To evaluate clinical safety and efficacy of the angiostatic agent anecortave acetate for treatment of subfoveal choroidal neovascularization secondary to AMD. METHODS: 128 patients were randomized to placebo treatment or one of three anecortave acetate doses. Study medication was administered as a posterior juxtascleral injection onto the posterior scleral surface. Best-corrected logMAR vision was obtained at baseline and follow-up visits. Fluorescein angiograms were evaluated for eligibility before enrollment and posttreatment. RESULTS: Six months after a single treatment, visual acuity (mean change from baseline logMAR values) was significantly better (P = 0.003) after anecortave acetate 15 mg than placebo. More patients treated with anecortave acetate 15 mg than placebo maintained vision (88% versus 70%, P = 0.080), especially those with predominantly classic lesions (92% versus 65%, P = 0.021). Anecortave acetate 15 mg inhibited lesion growth significantly better than placebo (P = 0.001). Trends favoring the other doses over placebo were observed for vision preservation and lesion inhibition, but statistical significance was not achieved. The Independent Safety Committee overseeing this study identified no clinically relevant treatment-related changes. CONCLUSION: Anecortave acetate 15 mg is safe and effective for preserving or improving vision and for inhibiting lesion growth in patients with subfoveal AMD.

Recent advances in the management of age-related macular degeneration.

Choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) can cause rapid and severe central vision loss in many older people. Until recently, the only treatment proven beneficial was thermal laser photocoagulation, which was applicable to only a small subset of patients. Furthermore, the thermal laser damaged the retina overlying the CNV, which is especially problematic for lesions involving the foveal center. Photodynamic therapy is a new treatment consisting of intravenous infusion of a drug that is then activated by a low-energy laser, causing damage to CNV. Photodynamic therapy with verteporfin (Visudyne, Novartis AG) has been shown to reduce the risk of moderate and severe vision loss in patients with predominantly classic subfoveal CNV secondary to AMD. With the advent of verteporfin therapy, eye care providers will play an increasingly important role in managing patients with AMD, especially in the early detection and rapid referral of appropriate cases.