Health policies that favor using ranibizumab (Lucentis) for treating eye disease in older people over safety concerns for a cheaper alternative should take account of a new Cochrane Review published on Sept. 14. The researchers looked at the results of studies which compared the safety of two drugs used for treating age-related macular degeneration, ranibizumab and bevacizumab (Avastin). Contrary to what was argued by some experts, the review has found that the cheaper drug, bevacizumab, does not appear to increase deaths or serious side-effects compared with ranibizumab in people with neovascular age-related macular degeneration.

Bevacizumab was developed to treat cancer, while ranibizumab is marketed specifically for age-related macular degeneration. The authors conclude that health policies that favor the much more costly ranibizumab instead of bevacizumab for macular degeneration, for reasons of safety, are not supported by current randomized controlled trial evidence. A larger Cochrane Review, which will assess additional sources of evidence, is now planned to help reduce the remaining uncertainties around the relative benefits and safety of these drugs.

Bevacizumab and ranibizumab are related biological drugs that work to prevent the abnormal growth and swelling of blood vessels that are characteristic signs of macular degeneration. Although the beneficial effects of the two drugs are believed to be similar, only ranibizumab has been licensed as a treatment for macular degeneration; bevacizumab is currently approved only as a cancer therapy. Despite this, an unlicensed preparation of bevacizumab is often used off-label as treatment for macular degeneration, because it is cheaper than ranibizumab. It has been suggested that the two drugs have different safety profiles, such that bevacizumab might cause more systemic harms, and the review investigated this concern.

Lorenzo Moja, from the University of Milan, stated, “This review represents an important step forward in the knowledge about differences in systemic harms between bevacizumab and ranibizumab and mitigates past disputes around evidence. The review authors were able to collect evidence from nine trials, including three unpublished studies, while most other reviews focus primarily on published data”. He continues “This result was possible through the collaborative effort of researchers across several countries (France, Germany, Italy, UK and the United States), many of who were involved in the original trials. It shows a remarkable level of commitment of trialists and health-care systems to answer an important clinical question. I am unaware of other examples with such a large number of head-to-head, non-industry-sponsored RCTs.”

Editor in Chief of The Cochrane Library, Dr. David Tovey, added, “This review addresses a question of immense importance to health systems in many countries. One of the many considerations in decision-making at policy level is not just understanding how effective treatments are, but also weighing up evidence of their safety.”

Endothelial Cell Dysfunction Implicated in Glaucoma
In a unique study of human ocular cells, a multi-institution research team led by a biomedical engineer at Northwestern University has found a new glaucoma culprit: a mechanical dysfunction of endothelial cells.

The researchers found that endothelial cells from eyes with glaucoma are stiffer than cells from healthy eyes. This stiffness limits the cells’ ability to deform and allow aqueous humor to cross the endothelium and drain into Schlemm’s canal. The findings were published in the online early edition of the Proceedings of the National Academy of Science.

“There is no cure for glaucoma, which affects more than two million Americans,” said Mark Johnson, PhD, the senior author of the study. “Our work shows that cells of this endothelial layer act as mechanical gates. Therapeutic strategies that alter the stiffness of these cells potentially could lead to a cure for this debilitating disease.”

Dr. Johnson is a professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science and a professor of ophthalmology at Northwestern University Feinberg School of Medicine.

“The work appears to be one of the first times that the methods of mechanobiology—the study of the mechanical characteristics of cells—have been used to show that dysfunctional cell mechanics lies at the heart of a disease process,” Dr. Johnson said.
The review included nine randomized controlled trials, none of which was supported by manufacturers of either treatment, involving a total of 3,665 participants, comparing bevacizumab with ranibizumab. The drugs were given for up to two years. The review found the systemic safety of bevacizumab for macular degeneration appeared to be similar to that of ranibizumab, except for gastrointestinal disorders. Although no statistically significant differences between the treatments were found, the review does not exclude the possibility that either treatment is less harmful than the other. The researchers estimated that if 1,000 people were treated with ranibizumab for one to two years, 34 would die; if treated instead with bevacizumab, between 27 and 53 would die. If 1,000 people were treated with ranibizumab, 222 would experience one or more serious systemic adverse events. If 1,000 people were treated instead with bevacizumab, between 200 and 291 would experience such an event.

They rated the overall quality of the evidence as low to moderate because of the uncertainty of the findings, and due to other study limitations. Additionally, the review authors indicated that they could not fully assess the quality of three of the studies as they had not yet been published.

Probes May Speed DR Detection
A new study published in
the September issue of The FASEB Journal identifies a novel strategy to diagnose diabetic retinopathy before irreversible structural damage has occurred. This advance involves quantifying the early molecular changes caused by diabetes on the endothelium of retinal vessels. Using new probes, scientists were able to distinguish the early molecular development of diabetic retinopathy.

“My goal is to establish a versatile clinical tool that alerts of a disease process right when the first molecular changes take place. This will then provide ample opportunity to act, as opposed to merely acknowledge that there is structural damage that we cannot do anything about,” said Ali Hafezi-Moghadam, MD, PhD, a researcher involved in the work from the Center for Excellence in Functional and Molecular Imaging at Brigham and Women’s Hospital and Harvard Medical School in Boston. “Here, we have shown it in an important disease, the diabetic retinopathy, but there is no reason to stop there.”

Dr. Hafezi-Moghadam and colleagues identified a target on the intraluminal surface of the retinal vessels that is expressed at higher levels in diabetes. They found significantly more vascular endothelial growth factor receptor 2 (VEGFR-2) in the diabetic micro-vessels compared to control. They then custom-generated molecular probes and characterized their binding properties. Light-based live imaging was then used to quantify binding interaction. An unexpected finding in this work was that not only was VEGFR-2 higher in the retinas of diabetic animals as well as humans, but the molecule was found in the retinal micro-vessels, not in the larger vessels. When the imaging probes were injected into the blood stream of living normal and diabetic animals, they circulated throughout the animal’s vasculature. With the help of live imaging of the retinal vessels, it was possible to visualize the interaction of individual probes with their endothelial targets. The probes transiently interacted with the intraluminal surfaces. In comparison, control probes with a surface moiety that does not interact with the inner vascular lumen freely flowed through the retinal micro vessels. Since the probe interaction with the inner vessel wall can be deduced to individual molecular interactions, the information gained from this study provides quantitative knowledge of target molecules in the retinal micro vessels.

“This study should be a huge eye-opener for doctors hoping to prevent eye disease resulting from diabetes,” said Gerald Weissmann, MD, editor in chief of The FASEB Journal. “This study shows that it is possible to do this, and the next step is to make this accessible at the clinical level. The sooner doctors can detect that their patients might have a vision problem, the more time they have to save someone’s sight.”

Native American Ancestry a Risk Factor for DR
New research led by
the University of Southern California Eye Institute, part of Keck Medicine of USC, shows for the first time that Native American ancestry is a significant risk factor for vision-threatening diabetic retinopathy among Latinos with type II diabetes. Diabetic retinopathy is the leading cause of blindness in working-age adults in the United States, affecting more than 4 million Americans age 40 and older. The research was published online in Investigative Ophthalmology & Visual Science.

“This is the first study, to our knowledge, that examines the contribution of genetic ancestry in vision-threatening diabetic eye disease in Latinos,” said USC Eye Institute Director Rohit Varma, MD, MPH, professor and chair of the Department of Ophthalmology at Keck and the study’s principal investigator. “Previous research has shown that Latinos have a higher prevalence of diabetic retinopathy than non-Hispanic Whites and African-Americans. Our findings suggest that one contributor to this heavy burden may be due to their Native American ancestry.”

Latinos are a diverse group of people typically with a varying mixture of Native American, European and African ancestry. Dr. Varma’s research team examined data from 944 Latinos with type II diabetes from the Los Angeles Latino Eye Study (LALES), the largest population-based study of eye disease in that ethnic group. The participants in the study were 40 years of age or older and hailed from the city of La Puente in Los Angeles County, Calif. Ninety-five percent of them were of Mexican origin. Of the 944 people with type II diabetes, 135 had vision-threatening diabetic retinopathy while 809 did not.

Using genetic assays and detailed ophthalmologic examinations, the team found that individuals with more than 50 percent Native American ancestry had an 87 percent higher chance of also having vision-threatening diabetic retinopathy compared to those who had less than 50 percent Native American ancestry, even after controlling for known risk factors for the disease.

“Our next steps will be to try to narrow down which genomic locations among those with a Native American origin might be contributing to boosting the risk for developing severe diabetic retinopathy,” said Xiaoyi Gao, PhD, the study’s first author, who started his research at USC. Dr. Gao is now an associate professor of ophthalmology in the University of Illinois, Chicago College of Medicine.  REVIEW