In September, the Food and Drug Administration approved Regeneron Pharmaceuticals’ Eylea (aflibercept) injection for the treatment of macular edema following central retinal vein occlusion. The recommended dose for Eylea is 2 mg every four weeks.
The approval of Eylea for macular edema following CRVO was based on data from the Phase III COPERNICUS and GALILEO studies. In both studies, the primary efficacy end point was the proportion of patients who gained at least 15 letters of best-corrected visual acuity at 24 weeks compared to baseline as measured by ETDRS. Results for the Eylea 2-mg monthly group were superior to those for the sham control group for the primary endpoint.
The safety and efficacy of Eylea in the treatment of macular edema following CRVO were assessed in two randomized, multicenter, double-masked, sham-controlled studies: COPERNICUS and GALILEO. A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies. In both, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every four weeks, or sham injections (control group) administered every four weeks for a total of six injections. After six monthly injections, patients continued to receive Eylea treatment during weeks 24 to 52 only if they met pre-specified retreatment criteria (PRN), except for patients in the sham control group in the GALILEO study who continued to receive sham injections through week 52. Patients ranged in age from 22 to 89 years with a mean of 64 years.
In the COPERNICUS study, after six months, 56 percent of patients receiving Eylea 2 mg monthly gained at least 15 letters of BCVA from baseline, as measured by ETDRS, compared to 12 percent of patients receiving sham injections (p<0.01), the primary endpoint of the study. Patients receiving Eylea 2 mg monthly gained, on average, 17.3 letters of vision compared to a mean loss of 4.0 letters with sham control injections (p<0.01), a secondary endpoint.
In the GALILEO study, after six months, 60 percent of patients receiving EYLEA 2 mg monthly for the first six months, gained at least 15 letters of BCVA from baseline, compared to 22 percent of patients receiving sham injections (p<0.01) during this time, the primary endpoint of the study. Patients receiving Eylea 2 mg monthly gained, on average, 18 letters of vision compared to a mean gain of 3.3 letters with sham control injections (p<0.01), a secondary endpoint.
UK Group: ‘Major Breakthrough’ in Dry AMD
University of Kentucky researchers, led by Jayakrishna Ambati, MD, have made an exciting finding in the dry form of age-related macular degeneration. Geographic atrophy causes blindness in millions of individuals due to death of retinal pigment epithelial cells. The paper, “ERK1/2 Activation is a Therapeutic Target in Age-Related Macular Degeneration” appears in the Aug. 21 online issue of the Proceedings of the National Academy of Sciences.
|Expanded Labeling for B + L’s Besivance|
The Food and Drug Administration has granted additional labeling indications to Bausch + Lomb for its Besivance (besifloxacin ophthalmic suspension) 0.6% eye drop, including an indication to treat bacterial conjunctivitis infections caused by susceptible isolates of Pseudomonas aeruginosa, a rare but potentially virulent pathogen that can be associated with serious eye conditions, such as corneal ulcers and blindness. Three other significant ocular pathogens added to the indications granted for the Besivance eye drop include Aerococcus viridians, Moraxella catarrhis and Staphylococcus warneri.
Besivance suspension has been approved in the United States for the treatment of bacterial conjunctivitis since 2009 and is the first and only dual-halogenated chlorofluoroquinolone in topical ophthalmic use. It has demonstrated potent activity and high rates of eradication against problematic multi-drug resistant Gram-positive organisms, such as Methicillin-resistant S. aureus (MRSA)/Methicillin-resistant S. epidermidis (MRSE), and Gram-negative pathogens, such as P. aeruginosa, that can cause serious eye infections.
“Many eye-care physicians consider Pseudomonas aeruginosa as a more serious threat to ocular health than MRSA,” said Terrence P. O’Brien, MD, professor of ophthalmolofy at Bascom Palmer Eye Institute of the University of Miami, Fla. “With the additional indication of Pseudomonas aeruginosa as well as the other important ocular pathogens covered by besifloxacin 0.6%, physicians now have a potent, broad-spectrum, branded prescription eye drop to rapidly treat bacterial conjunctivitis caused by the most common serious sight-threatening pathogens.”
Dr. Ambati, a professor of physiology, and professor and vice chair of ophthalmology and visual sciences at UK, is a leader in the field of macular degeneration research. Previous research from the Ambati laboratory published in the journal Nature
showed that in human eyes with geographic atrophy there is a deficiency of the enzyme DICER1, leading to accumulation of toxic Alu RNA molecules in the retinal pigmented epithelium. Another paper published in the journal Cell
showed that when these RNAs build up in the eye they trigger activation of an immune complex known as the NLRP3 inflammasome. In turn, this leads to the production of a molecule known as IL-18, which causes death of retinal pigmented epithelial cells and vision loss by activating a critical protein known as MyD88.
Importantly, Dr. Ambati and colleagues found evidence that activity of the inflammasome, IL-18, and MyD88 were all increased in human eyes with GA. They then showed that blocking any of these components could prevent retinal degeneration in multiple disease models. The researchers are excited that blocking these pathways could herald a new potential therapy for GA, for which there is no approved treatment.
In the current paper, the authors show that Alu RNA, which increases following DICER1 deficit, activates a family of enzymes known as extracellular-signal-regulated kinases (ERK) 1/2. ERK 1/2, which are also known as classical mitogen-activated protein kinases (MAPKs), were found to be increased in the RPE of human eyes with GA and shown to be key mediators of RPE cell death. This work further defines the mechanisms of cell death in human GA and identifies a new therapeutic target for the dry form of AMD.
Oraya INTREPID Study Achieves Primary Endpoint
During the 12th EURETINA Congress in Milan, Italy, Oraya Therapeutics announced that its INTREPID trial of radiation therapy for wet age-related macular degeneration achieved its primary end point. The INTREPID study is the first sham-controlled, double-masked trial to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. A total of 21 sites in five European countries participated in the trial with a total enrollment of 230 subjects.
|An illustration of Oraya Therapeutic’s iRay radiotherapy system, which is being tested in conjunction with anti-VEGF injections to treat wet age-related macular degeneration.|
Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator for the trial, presented the results on September 8. He reported that the trial demonstrated a statistically significant reduction in as-needed injections after one year. The actively treated patients required approximately 35 percent fewer injections than the sham group with similar or in some cases, better visual acuity outcomes. No radiation-related adverse events were experienced at the one-year end point, including 60 subjects already at two-year follow-up. In addition, a defined population sub-group comprising roughly half of the study participants experienced even lower injection rates, while exhibiting meaningful vision benefit compared to sham.
Dr. Jackson stated that, “the year-one results of the INTREPID trial are very encouraging for people with wet AMD—the prospect of fewer eye injections will appeal to all those receiving anti-VEGF therapy, and for certain subsets there is the added advantage of an improved visual outcome. Whilst it will be important to monitor safety over a longer period, the results so far suggest a favorable safety profile.”
“We are very pleased that the results of the INTREPID trial have validated the benefits of the Oraya Therapy for patients, clinicians and health care providers,” stated Jim Taylor, CEO of Oraya Therapeutics. “It is rare to have a new therapy that demonstrates improved patient outcomes while simultaneously offering the potential to significantly reduce treatment burden and costs. To have these benefits validated in a rigorous clinical trial is very rewarding, and we are exceptionally grateful to the patients and clinicians who participated in this important study. In the coming weeks, we will be introducing the therapy on a commercial basis in several European markets, and we look forward to the opportunity to make a significant positive impact on the treatment of wet AMD in the months and years ahead.”
24-Hour IOP Monitoring Shows Some Promise
Continuous 24-hour intraocular pressure monitoring with a contact lens sensor demonstrated good safety and tolerability in a recent Archives of Ophthalmology study published online on Aug. 13, 2012. Forty patients with or suspected of having glaucoma participated in two 24-hour IOP monitoring sessions at a one-week interval. Patients pursued daily activities, and sleep behavior was not controlled. Incidence of adverse events and tolerability (visual analog scale score) were assessed. Reproducibility of signal patterns was assessed using Pearson correlations.
The recorded IOP patterns showed fair to good reproducibility, suggesting that data from continuous 24-hour IOP monitoring may be useful in the management of patients with glaucoma, the authors conclude. REVIEW