Eye injections of the drug Avastin (bevacizumab) bring no greater risk of endophthalmitis than injections with the much more expensive drug Lucentis (ranibizumab) made by the same company, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings were published in JAMA Ophthalmology.

The study, based on insurance claims data from across the United States, was conducted in response to reports of Avastin-related endophthalmitis, which led the Food and Drug Administration recently to propose significant restrictions on use of the drug for eye conditions.

“Our analysis of a national dataset shows that the risk for endophthalmitis is no higher with Avastin and hints that there may actually be a lower endophthalmitis risk compared to Lucentis, so the proposed FDA restrictions for Avastin might have the unintended consequence of increasing the infection risk for patients,” said senior author Brian L. VanderBeek, MD, MPH, an assistant professor of ophthalmology at Penn.

Dr. VanderBeek and his colleagues’ findings come after years of tension between eye doctors and Avastin’s maker Genentech over the drug’s ophthalmic use.

Avastin is an injectable solution of monoclonal antibodies targeted at the blood vessel growth factor VEGF. It was the first drug designed to inhibit angiogenesis, and was approved by the FDA in 2004 for treating colorectal cancers—which typically boost angiogenesis to keep themselves well supplied with oxygen and nutrients.

Common age- and diabetes-related retinal diseases, such as wet macular degeneration, also result in part from VEGF-driven processes, so ophthalmologists soon began to use Avastin off-label to treat these conditions. Avastin as distributed for cancer treatment is frequently repackaged by compounding pharmacies into smaller doses suitable for use in the eyes, which drives the cost of the medication down to about $50 per eye injection.

Genentech has also developed a similar eye-specific angiogenesis-inhibiting, anti-VEGF monoclonal antibody, Lucentis. It was FDA-approved in 2006 and costs as much as $2,000 per dose, even though it is closely related to the Avastin antibody and multiple clinical trials have found that the two drugs have virtually the same efficacy.

AstraZeneca Cancer Drug Fails Uveal Melanoma Phase III Trial 

AstraZeneca’s cancer treatment selumetinib failed to significantly prolong survival in a study on melanoma that has spread to the eye, a late-stage setback for a drug once considered a bright spot in the company’s oncology pipeline.

In a 152-patient Phase III trial, a combination of selumetinib and the common chemotherapy dacarbazine failed to improve progression-free survival compared with the old drug alone, the company said. Uveal melanoma affects about 2,000 Americans each year.

Selumetinib’s failure comes on the heels of some promising mid-stage data in which the treatment more than doubled progression-free survival in uveal melanoma patients, jumping from seven weeks in the chemotherapy arm of the study to 15.9 weeks in the drug arm. Those results, presented at 2013’s American Society of Clinical Oncology meeting, raised hopes that AstraZeneca was on track to win the first-ever approval for uveal melanoma, which has no effective therapies.

The drug continues to be studied for lung and thyroid cancer, and neurofibromatosis. 
To promote the use of the more expensive Lucentis, Genentech announced in 2007 that it would block Avastin’s ophthalmic use by prohibiting its sale to compounding pharmacies, but the company backed away from this plan after strong protests from eye doctors.

Then in 2012, a few reports in the media noted endophthalmitis outbreaks following repackaged Avastin injections. The endophthalmitis outbreaks were limited to specific compounding pharmacies. Amid a general concern over potential substandard practices at compounding pharmacies nationally, the FDA announced in February of this year that it planned to restrict the ophthalmic use of Avastin to the five-day period following the repackaging of the drug by a compound pharmacy.

“This would effectively prevent most ophthalmic use of Avastin,” Dr. VanderBeek said. “Compounding pharmacies require 14 days after repackaging just for sterility testing, and without this critical step, ophthalmologists will lack confidence in the safety of the repackaged Avastin and unlikely to use it.”

To get a better picture of Avastin’s true endophthalmitis risk, Dr. VanderBeek and his colleagues looked at the medical claims database for a large American insurance company, covering the years 2005 through 2012. The data they reviewed contained no information identifying patients.

Analyzing the 296,565 injections of Avastin and 87,245 injections of Lucentis that met their inclusion criteria, the Penn researchers found 49 and 22 cases, respectively, of endophthalmitis. Thus the rate of the complication in this dataset was very low, 0.017 percent for Avastin, and still low but slightly higher, 0.025 percent, for Lucentis.

The 35-percent lower rate of end-ophthalmitis seen in Avastin wasn’t statistically significant, but the authors say the data at least suggest strongly that on a nationwide basis, Avastin repackaged by compounding pharmacies doesn’t involve greater endophthalmitis risk than Lucentis packaged by its manufacturer.

The American Academy of Ophthalmology has been lobbying against the proposed new FDA regulations. “The findings from our study support their stance,” Dr. VanderBeek said. Co-authors of the study were Sarah G. Bonaffini and Liyuan Ma, both of Penn Medicine at the time of the research.

New Clues to AMD Vision Loss
Scientists have identified a
pathway that leads to the formation of atypical blood vessels that can cause blindness in people with age-related macular degeneration.

In this image of the retina, normal blood vessels (green) surround a clump of new, abnormal vessels that has formed beneath the center of the retina. Scientists at Washington University School of Medicine have identified a molecular pathway that leads to the formation of such blood vessels. (Image courtesy Washington University School of Medicine.) 

The research, at Washington University School of Medicine in St. Louis, sheds light on one of the leading causes of blindness in industrialized countries and offers potential targets for treating the disease.

The study was published online Aug. 11 in the journal Nature Communications.

“Our research increases our understanding of how specific immune cells can contribute to vision loss in macular degeneration, and it also may help us identify treatments by giving us a molecular pathway to target,” said principal investigator and retina specialist Rajendra S. Apte, MD, PhD. “When we inhibit this pathway, we can alter the immune cells and interfere with abnormal blood vessel growth in mice. Doing so might open therapeutic avenues to halt vision loss or even restore sight in people who have macular degeneration, the leading cause of blindness in people over 50.”

Dr. Apte, the Paul Cibis distinguished professor of ophthalmology and visual sciences at the School of Medicine, has spent years studying the immune system in the eye to distinguish changes related to aging from those related to disease. In earlier work, he found that a cell-signaling molecule called interleukin-10 plays a role in the formation of blood vessels involved in the wet form of macular degeneration.

Before vision loss occurs, IL10 levels increase in the eye, as do the number of specific immune cells, M2 macrophages. These macrophages are known to contribute to the development of damaging blood vessel growth beneath the retina.

Until now, though, how IL10 actually contributed to the proliferation of macrophages and damaging blood vessels wasn’t well understood. So Dr. Apte and his colleagues engineered mice in which various cell-signaling pathways were disabled. Those experiments led them to discover that a specific signaling pathway involving a protein called STAT3 was activating and altering immune cells in the eye, and those cells then spurred the formation of harmful blood vessels.

Further, they examined eye tissue from patients treated in the 1980s and 1990s, when surgery to remove abnormal blood vessels from underneath the retina was routinely performed on patients with the wet form of macular degeneration. There, too, the same STAT3 protein that was abundant and active in M2 macrophages in mice also was found in high levels in the human tissue.

The findings suggest that the causes of damaging blood vessel growth in people are the same as what the researchers had observed in mouse models, Dr. Apte said. In both mice and in patients, abnormal blood vessel growth was linked to macrophages with high levels of the active form of STAT3.

That a cause of significant vision loss appears to be the same in mice and people is good news, Dr. Apte said, because some compounds can disrupt the actions of STAT3 in mice and keep the pathway from spurring blood vessel growth. Those same compounds may alter the course of macular degeneration in people with the condition.

“Now that we have a better idea of how these macrophages are activated at the molecular level, we may be able to use those drugs to halt or reverse the disease process,” Dr. Apte said.  REVIEW