Jeffrey S. Heier

Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.

OBJECTIVE Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab. DESIGN Double-masked, multicenter, parallel-group, active-controlled, randomized trials. PARTICIPANTS Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. INTERVENTION Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4). MAIN OUTCOME MEASURES The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures. RESULTS All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. CONCLUSIONS Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration: Two-Year Results of the ANCHOR Study

OBJECTIVE The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. DESIGN Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. PARTICIPANTS Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs. INTERVENTION Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). MAIN OUTCOME MEASURES The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored. RESULTS Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]). CONCLUSIONS In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Macular Edema Due to Retinal Vein Occlusion

OBJECTIVE To evaluate the safety and efficacy of dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc., Irvine, CA) compared with sham in eyes with vision loss due to macular edema (ME) associated with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). DESIGN Two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials (each of which included patients with BRVO and patients with CRVO). PARTICIPANTS A total of 1267 patients with vision loss due to ME associated with BRVO or CRVO. INTERVENTION A single treatment with DEX implant 0.7 mg (n = 427), DEX implant 0.35 mg (n = 414), or sham (n = 426). MAIN OUTCOME MEASURES The primary outcome measure for the pooled data from the 2 studies was time to achieve a > or =15-letter improvement in best-corrected visual acuity (BCVA). Secondary end points included BCVA, central retinal thickness, and safety. RESULTS After a single administration, the time to achieve a > or =15-letter improvement in BCVA was significantly less in both DEX implant groups compared with sham (P<0.001). The percentage of eyes with a > or =15-letter improvement in BCVA was significantly higher in both DEX implant groups compared with sham at days 30 to 90 (P<0.001). The percentage of eyes with a > or =15-letter loss in BCVA was significantly lower in the DEX implant 0.7-mg group compared with sham at all follow-up visits (P< or =0.036). Improvement in mean BCVA was greater in both DEX implant groups compared with sham at all follow-up visits (P< or =0.006). Improvements in BCVA with DEX implant were seen in patients with BRVO and patients with CRVO, although the patterns of response differed. The percentage of DEX implant-treated eyes with intraocular pressure (IOP) of > or =25 mmHg peaked at 16% at day 60 (both doses) and was not different from sham by day 180. There was no significant between-group difference in the occurrence of cataract or cataract surgery. CONCLUSIONS Dexamethasone intravitreal implant can both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with ME secondary to BRVO or CRVO and may be a useful therapeutic option for eyes with these conditions.

Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results

OBJECTIVE To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion (BRVO or CRVO). DESIGN Two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase followed by a 6-month open-label extension. PARTICIPANTS We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO. METHODS At baseline, patients received DEX implant 0.7 mg (n = 421), DEX implant 0.35 mg (n = 412), or sham (n = 423) in the study eye. At day 180, patients could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84 letters or retinal thickness was >250 μm. MAIN OUTCOME MEASURES The primary outcome for the open-label extension was safety; BCVA was also evaluated. RESULTS At day 180, 997 patients received open-label DEX implant. Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively. In the group receiving two 0.7-mg DEX implants (n = 341), a ≥ 10-mmHg intraocular pressure (IOP) increase from baseline was observed in (12.6% after the first treatment, and 15.4% after the second). The IOP increases were usually transient and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after the second treatment. A ≥ 15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively. CONCLUSIONS Among patients with macular edema owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over 12 months. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety of the 2 implants were similar with the exception of cataract progression. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Twelve-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-related Macular Degeneration

OBJECTIVE To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS Patients aged ≥ 50 years with subfoveal wet AMD. METHODS Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. RESULTS At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 μm, -161.2 μm, -163.3 μm, and -172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

A Phase IIIb Study to Evaluate the Safety of Ranibizumab in Subjects with Neovascular Age-related Macular Degeneration

OBJECTIVE To evaluate the safety and efficacy of intravitreal ranibizumab in a large population of subjects with neovascular age-related macular degeneration (AMD). DESIGN Twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial. PARTICIPANTS A total of 4300 subjects with angiographically determined subfoveal choroidal neovascularization (CNV) secondary to AMD. METHODS Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses. Dose groups were stratified by AMD treatment history (treatment-naïve vs. previously treated). Cohort 1 subjects were retreated on the basis of optical coherence tomography (OCT) or visual acuity (VA) criteria. Cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. MAIN OUTCOME MEASURES Safety outcomes included the incidence of ocular and nonocular adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included changes in best-corrected VA over time. RESULTS Some 81.7% of cohort 1 subjects and 49.9% of cohort 2 subjects completed the 12-month study. The average total number of ranibizumab injections was 4.9 for cohort 1 and 3.6 for cohort 2. The incidence of vascular and nonvascular deaths during the 12-month study was 0.9% and 0.7% in the cohort 1 0.3 mg group, 0.8% and 1.5% in the cohort 1 0.5 mg group, and 0.7% and 0.9% in cohort 2, respectively. The incidence of death due to unknown cause was 0.1% in both cohort 1 dose groups and cohort 2. The number of vascular deaths and deaths due to unknown cause did not differ across cohorts or dose groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the 0.3 mg and 0.5 mg groups and cohort 2, respectively. At month 12, cohort 1 treatment-naïve subjects had gained an average of 0.5 (0.3 mg) and 2.3 (0.5 mg) VA letters and previously treated subjects had gained 1.7 (0.3 mg) and 2.3 (0.5 mg) VA letters. CONCLUSIONS Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA. Future investigations will seek to establish optimal dosing regimens for persons with neovascular AMD. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Ranibizumab for Macular Edema Due to Retinal Vein Occlusions: Long-term Follow-up in the HORIZON Trial

PURPOSE To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO). DESIGN Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials. PARTICIPANTS We included 304 patients who completed BRAVO and 304 patients who completed CRUISE. METHODS Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria. MAIN OUTCOME MEASURES Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness. RESULTS In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), -2.3 (0.3/0.5 mg), and -0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was -4.2 (sham/0.5 mg), -5.2 (0.3/0.5 mg), and -4.1 (0.5 mg), respectively. CONCLUSIONS No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months.

One-year outcomes of the da VINCI study of VEGF trap-eye in eyes with diabetic macular edema

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.

The DA VINCI Study: Phase 2 Primary Results of VEGF Trap-Eye in Patients with Diabetic Macular Edema

PURPOSE To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME). DESIGN Multicenter, randomized, double-masked, phase 2 clinical trial. PARTICIPANTS A total of 221 diabetic patients with clinically significant macular edema involving the central macula. METHODS Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter. MAIN OUTCOME MEASURES Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks. RESULTS Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5 to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group (P ≤ 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+, and 15+ letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from -127.3 to -194.5 μm compared with only -67.9 μm in the laser group (P = 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were generally consistent with those seen with other intravitreal anti-VEGF agents. CONCLUSIONS Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME.

Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study.

PURPOSE To evaluate intravitreal aflibercept injections (IAI; also called VEGF Trap-Eye) for patients with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Randomized controlled trial. METHODS This multicenter study randomized 189 patients (1 eye/patient) with macular edema secondary to CRVO to receive 6 monthly injections of either 2 mg intravitreal aflibercept (IAI 2Q4) (n = 115) or sham (n = 74). From week 24 to week 52, all patients received 2 mg intravitreal aflibercept as needed (IAI 2Q4 + PRN and sham + IAI PRN) according to retreatment criteria. The primary endpoint was the proportion of patients who gained ≥15 ETDRS letters from baseline at week 24. Additional endpoints included visual, anatomic, and quality-of-life NEI VFQ-25 outcomes at weeks 24 and 52. RESULTS At week 24, 56.1% of IAI 2Q4 patients gained ≥15 letters from baseline compared with 12.3% of sham patients (P < .001). At week 52, 55.3% of IAI 2Q4 + PRN patients gained ≥15 letters compared with 30.1% of sham + IAI PRN patients (P < .001). At week 52, IAI 2Q4 + PRN patients gained a mean of 16.2 letters of vision vs 3.8 letters for sham + IAI PRN (P < .001). The most common adverse events for both groups were conjunctival hemorrhage, eye pain, reduced visual acuity, and increased intraocular pressure. CONCLUSIONS Monthly injections of 2 mg intravitreal aflibercept for patients with macular edema secondary to CRVO resulted in a statistically significant improvement in visual acuity at week 24, which was largely maintained through week 52 with intravitreal aflibercept PRN dosing. Intravitreal aflibercept injection was generally well tolerated.