In an NIH-supported clinical trial comparing three drugs for diabetic macular edema, Eylea (aflibercept) provided greater visual improvement, on average, than did Avastin (bevacizumab) or Lucentis (ranibizumab) when vision was 20/50 or worse at the start of the trial. However, the three drugs resulted in similar average improvement when starting vision was 20/40 to 20/32. Investigators found no major differences in the safety of the three drugs. The trial was funded by the National Eye Institute, part of the National Institutes of Health.
“This comparative effectiveness study will help doctors and patients make informed decisions when choosing treatments for diabetic macular edema,” said NEI Director Paul A. Sieving, MD, PhD. The trial was conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net), which is funded by NEI. The results were published online in the New England Journal of Medicine.
DME can occur in people with diabetic retinopathy, a type of diabetic eye disease that can cause the growth of abnormal blood vessels in the retina. The macula is the area of the retina used when looking straight ahead, for tasks such as reading, driving and watching television. Macular edema occurs when fluid leaks from retinal blood vessels and accumulates in the macula, distorting vision. Macular edema can arise during any stage of diabetic retinopathy and is the most common cause of diabetes-related vision loss. About 7.7 million Americans have diabetic retinopathy. Of these, about 750,000 have DME.
DRCR.net investigators enrolled 660 people with macular edema at 88 clinical trial sites across the United States. When the study began, participants were 61 years old on average, and had had type 1 or type 2 diabetes 17 years on average. Only people with a visual acuity of 20/32 or worse were eligible to participate. At enrollment, about half the participants had 20/32 or 20/40 vision, and the other half had 20/50 or worse vision. In many states, a corrected visual acuity of 20/40 or better in at least one eye is required for a driver’s license that allows both day- and nighttime driving.
Each participant was randomly assigned to receive Eylea (2.0 milligrams/0.05 milliliter), Avastin (1.25 mg/0.05 mL) or Lucentis (0.3 mg/0.05 mL). Participants were evaluated monthly and received the assigned study drug by injection directly into the eye until the DME resolved or stabilized. Additionally, laser treatment was given if DME persisted without continual improvement after six months of injections. Laser treatment alone was the standard treatment for DME until widespread adoption of these drugs a few years ago.
All three drugs target vascular endothelial growth factor, which can cause leakage from blood vessels and the growth of new, abnormal blood vessels. Anti-VEGF drugs work for DME by reducing vascular leakage. Based on Medicare allowable charges, the per-injection costs of each drug at the doses used in this study were about $1,960 for Eylea, about $70 for Avastin and about $1,200 for Lucentis. During the year-long study, participants on Avastin and Lucentis received, on average, 10 injections, versus nine for those on Eylea.
One year after starting treatment, vision had improved substantially for the majority of trial participants. When visual acuity was 20/32 or 20/40 at the start of the trial, vision improved on average almost two lines on an eye chart in all three treatment groups. In contrast, for participants whose visual acuity was 20/50 or worse at the start of the trial, Eylea improved vision on average almost four lines, Avastin improved vision on average almost 2.5 lines, and Lucentis improved vision on average almost three lines.
“Eylea, Avastin and Lucentis yield substantial gains in visual acuity for most people with diabetic macular edema; however, on average, Eylea appears to provide additional benefit for patients who start treatment with moderate or worse vision loss,” said John A. Wells, MD, the lead author of the study and a retinal specialist at the Palmetto Retina Center, Columbia, S.C.
All three drugs reduced macular edema, but Eylea and Lucentis reduced the swelling more than Avastin. Also, during the study, a smaller percentage of participants on Eylea (36 percent) underwent laser treatment for persistent edema that did not resolve with anti-VEGF treatment alone, compared with those on Avastin (56 percent) or Lucentis (46 percent).
The DRCR.net is dedicated to facilitating multicenter clinical research of diabetic eye disease. The network formed in 2002 and comprises more than 350 physicians practicing at more than 140 clinical sites across the country. For more information, visit the DRCR.net website at drcrnet.jaeb.org. The study is registered as NCT01627249 at clinicaltrials.gov.
Steroid-Loaded Nanoparticles May Cut Rejection
There are about 48,000 corneal transplants done each year in the United States. Of these, 10 percent end up in rejection, largely due to poor medication compliance. This costs the health-care system and puts undue strain on clinicians, patients and their families.
Johns Hopkins Medicine researchers may have discovered a way to prevent rejection by using biodegradable nanoparticles that release needed medication into the eye after surgery. This discovery could solve the decades-old issue of medicine compliance and help patients achieve corneal transplant success.
“Medicine compliance is a major challenge in patient care,” says Walter Stark, MD, chief of the Division of Cornea, Cataract and External Eye Diseases at Johns Hopkins. “About 60 to 80 percent of patients don’t take medicine the way they are supposed to.”
In an animal study published in the March 10 issue of the Journal of Controlled Release, researchers looked into ways to alleviate the strain of adhering to a post-surgery treatment regimen that is sometimes hard to manage.
Rats that underwent a corneal graft surgery were randomly divided into four groups and were given various treatments. One group was injected weekly for nine weeks with a safe, biodegradable nanoparticle loaded with corticosteroids for timed release of medicine. The other three groups received weekly injections of saline, placebo nanoparticles and free dexamethasone sodium phosphate aqueous solution after surgery, respectively.
Treatments were given until the graft was clinically deemed as failed or until the nine-week test period concluded. Researchers looked at corneal transparency, swelling and growth of new blood vessels to decide if a graft had failed. For rats that received the nanoparticle loaded with corticosteroids, 65 percent of the treatment remained in the eye and did not leak within one week of the surgery. The concentration of the treatment also remained stronger than in the other three treatment groups. Additionally, there were no signs of swelling, and the cornea was clear throughout the test period. There were also far fewer instances of unwanted growth of new blood vessels in this group.
Two weeks after surgery, rats that received the placebo nanoparticle and saline injections had severe swelling, opaque corneas and unwanted growth of new blood vessels, all indicating graft failure. After four weeks, rats that received free dexamethasone sodium phosphate aqueous solution all had graft failure as well. The only group that showed successful corneal transplant was the group of rats that received the corticosteroid-loaded nanoparticle injections. The grafts were still viable in 100 percent of these rats.
“Corneal grafts are not easy to come by, and a lot of testing and time goes into ensuring the safe use of a graft for cornea transplant,” says Qingguo Xu, PhD, a research associate at the Center for Nanomedicine at the Wilmer Eye Institute at Johns Hopkins Medicine. “This is why we want to do a better job at making sure corneal transplants don’t end up in rejection, and our study illustrates a potentially better way.”
The steroid-loaded nanoparticle treatment group showed no signs of corneal transplant rejection. “That’s 100 percent efficacy, a very promising finding,” says Justin Hanes, PhD, director of the Center for Nanomedicine. “This type of treatment may also help prevent corneal transplant rejection in humans while making medicine adherence much easier on patients and their families.”
The nanoparticle loaded with medication could eliminate the need for a patient to remember to take his medicine—often multiple doses per hour—after a surgery, alleviating compliance risk. These types of drug delivery systems could be paired with other drugs and used in other conditions, such as glaucoma, macular degeneration and corneal ulcers, among others. The research team intends to continue the collaboration between engineering and medicine to look further into better ways to treat eye diseases.
Jetrea Data at 24 Months Shows Positive Results
ThromboGenics announced positive top-line results from its OASIS study with Jetrea (ocriplasmin). The OASIS study is a randomized, sham-controlled, double-masked study that followed up patients for 24 months post-injection. The study was designed to provide long-term controlled efficacy and safety data for Jetrea in patients being treated for symptomatic vitreomacular adhesion. The OASIS study is the first controlled study with Jetrea of its kind since the results of the pivotal Phase III program were announced in 2011. The study includes 24 month follow-up data, the longest period patients have been studied post-treatment with this novel medicine.
The key findings of the study were as follows:
• 41.7 percent of patients treated with Jetrea achieved VMA resolution at day 28 post-injection compared with only 6.2 percent of patients who received a sham injection (p<0.001); and
• The Jetrea safety profile in this 24 month follow-up study was consistent with the drug’s overall safety profile as known from the approved label. No new safety events were identified.
The OASIS data compare favorably with the results from the pivotal Phase III program with Jetrea where VMA resolution was seen in 26.5 percent of patients at day 28 post- injection. In the Phase III program 10.1 percent of patients treated with a placebo injection achieved VMA resolution (p<0.001).
The OASIS data shows the importance of improved patient selection in generating higher rates of VMA resolution with Jetrea. Recent real-world data has confirmed that access to more advanced diagnostic technology such as spectral-domain optical coherence tomography has enabled retina physicians to improve patient selection. As a result they have been able to select patients with focal VMA and an absence of epiretinal membrane, two criteria that have been shown to lead to better treatment outcomes with Jetrea.
Further analysis of all of the OASIS data, which will be interpreted with the help of retina physicians, is ongoing. The results from these analyses are planned to be released later this year. REVIEW