As a service to our readers, we are providing a recap of the major presentations at the American Academy of Ophthalmology (AAO) Annual Meeting in Chicago, held October 17 to 22, 2014. This feature is not intended to be all-inclusive, but rather reflects our editor’s picks as some of the top presentations at the meeting.
VIBRANT, NEWTON Trials Showed Aflibercept Effective in Treating RVO
Monthly intravitreal aflibercept (Eylea, Regeneron) injections provided significantly greater visual benefit and reduction in central retinal thickness (CRT) at 24 weeks compared with grid laser photocoagulation in eyes with branch retinal vein occlusion (BRVO) in the VIBRANT trial, Robert E. Leonard II, MD, reported.1
The VIBRANT trial was a phase 3, multicenter, randomized, double-masked, 52-week trial in treatment-naïve patients with unilateral macular edema secondary to BRVO diagnosed within 12 months and BCVA between 73 and 24 letters (20/40 to 20/320 Snellen equivalent) at enrollment. Patients received 2.0 mg intravitreal aflibercept injections every 4 weeks (n = 91) or laser (n = 92) from baseline to week 20. At week 24, receiving aflibercept were switched to 2.0 mg aflibercept every 8 weeks. Patients in the aflibercept arm who required rescue received laser at week 36; patients in the laser group who required rescue received 2.0 mg aflibercept monthly for 3 months, then every 8 weeks.
Of the patients in the aflibercept group, 53% gained at least 15 letters from baseline at week 24 compared with 27% in the laser group (P < .001). Mean improvement in BCVA was 17.0 letters for the aflibercept group and 6.9 letters for the laser group (P < .001). The mean reduction in CRT from baseline to week 24 was 280.5 μm in the aflibercept group and 128.8 μm in the laser group (P < .0001).
One eye in the aflibercept group had a traumatic cataract; it was the only serious ocular adverse event that occurred from baseline to week 24. The most common ocular adverse events were conjunctival hemorrhage (19.8%) and eye pain (4.4%).
Rahul Khurana, MD, presented on data from the NEWTON study. NEWTON is a phase 4, prospective, singlearm, single-center, interventional study testing whether the interval between injections in eyes with macular edema secondary to central retinal vein occlusion (CRVO) previously treated with bevacizumab (Avastin, Genentech) or ranibizumab (Lucentis, Genentech) increased when switched to aflibercept. Researchers enrolled patients who were previously treated with ranibizumab or bevacizumab for 6 months and had an occurrence of macular edema when extended beyond 4-week dosing intervals. Patients received 2.0 mg aflibercept on a treat-and-extend regimen.
Data from an interim analysis of 14 patients who switched to aflibercept showed that the macular edemafree period increased from an average of 39 days to 62 days, which was statistically significant. The increase in the numbers of days without edema ranged from 7 days to 49 days; 13 of 14 patients had an increase in interval.
- Leonard RE II. VIBRANT trial. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
- Khurana R. NEWTON study: intravitreal aflibercept injection for previously treated macular edema associated with central retinal vein occlusions. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
BRIGHTER/CRYSTAL Studies: PRN a Viable Strategy for BRVO, CRVO
Ongoing long-term trials support the safety and efficacy of intravitreal ranibizumab for treatment of BRVO and CRVO with dosing on an as-needed basis after stabilization of disease, said Jordi M. Mones, MD.1
The BRIGHTER study is an ongoing 24-month trial with patients randomized 2:2:1 to receive 0.5 mg ranibizumab (group 1), 0.5 ranibizumab plus laser (group 2), or laser alone (group 3) for treatment of BRVO. The open-label CRYSTAL study enrolled patients with CRVO for treatment with 0.5 mg ranibizumab. Patients in both studies received monthly injections until visual acuity was stable for 3 consecutive months, and were followed out to 12 months thereafter with treatment on an as-needed, or PRN, basis.
The BRIGHTER study confirmed the efficacy of ranibizumab for BRVO with no additional benefit of laser. There were mean gains of BCVA from baseline of 14.4 letters in group 1, 14.8 letters in group 2, and 6.0 letters in group 3 (P < .0001). Patients received a mean 4.8 injections in group 1 and 4.5 in group 2. There was no difference in visual acuity outcomes among patients who had ischemic versus nonischemic BRVO, Dr. Mones said. These likely represent patients who would not have been studied in pivotal clinical trials, Dr. Mones said.
The CRYSTAL study also enrolled patients with more advanced disease than studied in previous clinical trials for CRVO involving ranibizumab. Still, Dr. Mones said, mean change in BCVA at month 12 was 12.3 letters after a mean 8.1 injections. There were no new safety signals identified in either study, Dr. Mones said.
- Mones JM. BRIGHTER and CRYSTAL studies. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
MEAD: Dexamethasone Implant Superior to Sham
A higher percentage of patients with diabetic macular edema (DME) randomized to receive a dexamethasone intravitreal implant (Ozurdex, Allergan) had gains of at least 15 letters in BCVA compared with sham in the MEAD study, according to Anat Lowenstein, MD.1
The MEAD study was a 3-year, randomized, multicenter, masked, sham-controlled phase 3 study in which patients (n = 1048) were randomized to receive treatment via 0.7 mg dexamethasone intravitreal implant, 0.35 mg dexamethasone intravitreal implant, or sham. At 3 years, the mean number of treatments was 4.1 for the 0.7-mg group, 4.4 for the 0.35-mg group, and 3.3 for the sham group. The number of patients who met the primary efficacy endpoint of an improvement of at least 15 letters was 22.2% for the 0.7-mg group, 18.4% in the 0.35-mg group, and 12.0% in the sham group (P < .018).
The effects of the implant on BCVA compared with sham were similar to those in the total population for a number of patient subgroups, including men versus women, white versus nonwhite, those with diabetes duration less than 15 years versus more than 15 years, and DME duration less than 3 years versus more than 3 years.
Improvements in BCVA for patients in the treatment groups who were phakic were complicated by cataract development in year 2; improvements in BCVA were seen upon removal of cataract. Improvements in BCVA were consistent each year of the study in patients in the treatment groups who were pseudophakic.
- Lowenstein A. MEAD: diabetic macular edema trial subanalysis. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
Two Trials Showed Visual Gains at 52 Weeks with Conbercept
Patients with wet age-related macular degeneration (AMD) treated with conbercept had visual gains at 52 weeks in the AURORA and PHOENIX trials, according to Peter Kaiser, MD. Conbercept, an anti-VEGF agent, is approved in China for the treatment of wet AMD.1
The AURORA study was a phase 2 trial in which researchers treated patients (n =111) with either 0.5 mg conbercept or 2.0 mg conbercept for 3 months before randomizing patients to 1 of 4 treatment groups: 0.5 mg conbercept PRN, 0.5 mg conbercept monthly, 2.0 mg conbercept PRN, and 2.0 mg conbercept monthly. At 52 weeks, the 0.5-mg PRN group gained 14.3 letters, the 0.5-mg monthly group gained 9.3 letters, the 2.0-mg PRN group gained 12.4 letters, and the 2.0-mg monthly group gained 15.4 letters. Mean CRT improved in all groups over the same time period.
Dr. Kaiser also reported on the PHOENIX study, a phase 3 study in which treatment-naïve patients (n = 124) with wet AMD received 0.5 mg conbercept monthly for 3 months or sham monthly for 3 months. After 3 months, each group received 0.5 mg conbercept every 3 months. At 52 weeks, the continuous treatment group had a 9.9-letter gain in vision and the delayed treatment group had an 8.8-letter gain in vision; both gains were statistically significant from baseline. Each group also had significant reduction in CRT.
- Kaiser PK. Conbercept clinical trials. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
LUCAS: Similar VA Gains With Ranibizumab, Bevacizumab
Patients in the LUCAS study with active choroidal neovascular membrane and foveal-involving edema had similar improvements in visual acuity following treatment with bevacizumab or ranibizumab using a treatand- extend protocol, according to Karina Berg, MD.1
The mean change in visual acuity from baseline was not significantly different between the treatment groups. Patients in the ranibizumab group had a 6.6-letter change from baseline; patients in the bevacizumab group had a 7.4-letter change. The mean number of treatments in the ranibizumab group was 6.9; it was 8.2 in the bevacizumab group.
Retinal thickness decreased significantly for both treatment groups from baseline over 2 years, but no significant difference was noted between the groups. Patients in the ranibizumab group had a 122-μm reduction in retinal thickness from baseline; patients in the bevacizumab group had a reduction of 130 μm.
- Berg K. Lucentis compared to Avastin study: two-year results. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
DE-109 Effective in Treating Uveitis in SAKURA
DE-109 was effective in treating uveitis in SAKURA, according to Sunil K. Srivastava, MD.1
Dr. Srivastava presented data on SAKURA, a stage 3, multinational, multicenter, randomized, double-masked clinical trail testing the safety and efficacy of intravitreal injections of DE-109 for the treatment of active, noninfectious uveitis of the posterior segment. Researchers randomized patients (n = 347) to regiments of 44 μg, 440 μg, or 880 μg every 2 months. The primary endpoint of the study was the percentage of eyes with a vitreous haze (VH) score of 0 at month 5.
At month 5, 22.8% of eyes randomized to the 440-μg regimen had a VH score of 0, compared with 10.3% in the 44-μg arm and 16.6% in the 880-μg arm (P = .025). At month 5, 52.6% of subjects in the 440-μg arm achieved a VH score of 0 or 0.5+, compared with 43.1% in the 880-μg arm and 35% in the 44-μg arm (P = .008). Some improvements in VH score from baseline were seen as early at 2 weeks from start of treatment.
There were no cases of culture-positive endophthalmitis among the 3 study arms and 1 case of culture-negative endophthalmitis in the 880-μg arm. No patient in the 44-μg arm had noninfectious endophthalmitis, but 0.9% of patients in the 440-μg arm and 3.4% of patients in the 880-μg arm developed noninfectious endophthalmitis.
- Srivastava SK. Study assessing double-masked uveitis treatment (SAKURA) phase 3 trial. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
Phase 1b/2a Study of Tie2 Activator in DME
Therapeutic activation of the Tie2 pathway may provide a novel target for treatment of diabetic macular edema, said Daniel Matthew Miller, MD, PhD.1
Tie2 is know to maintain normal vessel function, and its deactivation by dephosphorylation leads to pericyte loss, endothelial cell degeneration, capillary occlusion, and blood vessel barrier break down, Dr. Miller said. “These changes provide the stimuli that ultimately leads to the angiogenic process,” he said.
The phase 1b/2a study enrolled patients into 1 of 4 cohorts treated with varying doses of AKB-9778, a novel Tie2 activator: 5 mg, 15 mg, 22.5 mg, and 30 mg. Patients self-administered AKB-9778 twice a day via a subcutaneous injection for 28 days. There was a 56-day observation period at the end of the treatment phase of the trial.
“Patients had worse macular edema at baseline and received more prior therapy than patients in RISE, RIDE, VIVID, or VISTA,” Dr. Miller said.
At the end of the study, there was an average of a 6.5-letter gain in the 3 cohorts considered active on therapy: 15 mg, 22.5, and 30 mg; the 5 mg dose was considered subtherapeutic, according to Dr. Miller. There was a strong correlation between resolution of macular edema and improvement in visual acuity. “Therapeutically activating Tie2 could lead to disease modifying effects above and beyond the standard of care,” Dr. Miller said.
Researchers are currently enrolling patients in the TIME-2 study, which will include 3 study cohorts: combination therapy AKB-9778 and intravitreal ranibizumab, AKB-9778 monotherapy, and ranibizumab monotherapy.
- Miller DM. Phase Ib/IIa study of AKB-9778, a novel Tie2 activator, in diabetic macular edema. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
DRCR.net Studies Updated
Lee M. Jampol, MD, delivered a series of updates on DRCR.net studies.1
Protocol M was a randomized trial which examined the effect personalized intervention had on A1C levels in patients with type 1 or type 2 diabetes. Researchers randomized patients to receive a personalized education plan or normal in-office advice. Researchers determined that no significant difference in A1C levels existed between the groups at 1 year.
Dr. Jampol reported that in a randomized clinical trial, use of topical nonsteroid drops did not improve vision in patients with noncenter-involving macular edema and good vision. Patients were randomized to receive nepafenac ophthalmic suspension drops (Nevanac, Alcon) or placebo 3 times per day for 1 year. At the end of 1 year, researchers found no difference in volume of macular edema and no difference in central subfield thickness.
Analysis of Protocol I data showed that over 3 years, 9.4% eyes that received repeated injections of ranibizumab had persistently elevated intraocular pressure (IOP), which was significant compared with the 3.3% of eyes in the sham group. The difference at 1 year (2.3% in the sham group vs 5.5% in the ranibizumab group) was not statistically significant.
“Repeated injections may be associated with increased risk of persistently elevated IOP as defined in our study,” Dr. Jampol said. Eyes which measured 22 mg Hg on 2 visits, eyes in which IOP increased by 6 mm Hg from baseline, or eyes that needed medical therapy or surgery to great elevated IOP were considered eyes with persistently elevated IOP.
Dr. Jampol reported that Protocol S, a 2-year study comparing panretinal photocoagulation versus anti- VEGF treatment for proliferative diabetic retinopathy, should be completed in December 2014.
- Jampol LM. Update on the DRCR studies. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.
PACORES: Bevacizumab Less Effective for AMD at 5 years
Bevacizumab was less effective at treating patients with AMD at 60 months compared with 36 months in PACORES, according to J. Fernando Arevalo, MD.1
Eyes with choroidal neovascularization secondary to AMD (n = 292) treated with at least 1 intravitreal injection of 1.25 mg bevacizumab were followed for 60 months. Dr. Arevalo reported that compared with 36 months of follow up, eyes had a decrease in visual acuity, from 20/150 to 20/250, at 60 months. The difference was statistically significant. There was also an increase in central macular thickness from 36 months to 60 months.
- Arevalo JF. Update of the results of the pan-American collaborative retina study group results. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 17-21, 2014; Chicago, Illinois.