CLINICAL TRIAL SPOTLIGHT

Looking Beyond the Macula

Some patients still don't respond to anti-VEGF agents. A new study will investigate the RPE to determine why.

Andrew E. Mathis, PhD, Medical Editor

Anti-VEGF agents are saving the sight of patients with age-related macular degeneration as no treatment ever before, but there remains a significant portion of patients who either respond suboptimally to these drugs or who fail to respond at all.

Theories abound as to why some patients do not respond to anti-VEGF agents as well as others do, and one such theory attributes the reaction of these patients to the response of the immune system to choroidal neovascularization. To this end, Genentech, the producer of ranibizumab (Lucentis) is cooperating with the University of California at Davis in a phase 2 trial that will investigate the role of antiretinal and anti-RPE antibodies in patients receiving ranibizumab.

David G. Telander, MD, PhD, who is assistant professor of ophthamology at UC Davis and the principal investigator on this trial, spoke with Retinal Physician about the trial.

THE ROLE OF ANTIBODIES IN AMD

Dr. Telander first explained the relationship between the immune system and incomplete response to anti-VEGF therapy. “We are trying to understand the 10% of patients with a slow or incomplete response to anti-VEGF therapy,” he said. “Our theory is that these patients may have a more robust immune response to the choroidal neovascular membrane, which may account for their decreased response.”

Simply put, when AMD results in choroidal neovascularization, the immune system attacks the CNV membrane. The inflammatory response that occurs allows the previously sequestered antigens in the RPE and retina to now be presented for immune response. These antiretinal and anti-RPE antibodies may or may not contribute to the process, but they do demonstrate the degree of inflammatory response. In some patients, the immune response is stronger than in others, and these patients may be the same patients who have a suboptimal response to anti-VEGF drugs.

Dr. Telander explained that his group is using the humoral response to exposed antigens as a marker of the degree of immune response. “Our interest is to see if this correlation exists, as antibodies are certainly found in AMD patients, and immunosuppression as been suggested to be protective,” he said.

The trial Dr. Telander is directing, which began enrolling patients at UC Davis earlier this year, will encompass four study arms. Two arms will consist of wet AMD patients who have been treated with ranibizumab, one of responders and one of nonresponders. The other two arms are made up of normal patients and patients with dry AMD.

Dr. Telander explained that part of the trial will go toward determining whether the antibodies being studied are genuinely being generated as a reaction to the CNV membrane. “Dry AMD patients are being included as a control to see if the antibodies are already being produced before the CNV membrane develops,” he said.

In total, the study will register 131 patients before it closes to new enrollment. Asked about the relatively large size of this study—particularly for a single-center trial—Dr. Telander discussed one of the inherent difficulties of this trial. “Our experience is that there is a lot of noise in the system,” he stated. “We have found that many normal patients produce antibodies, so there needs to be a large number of patients to isolate the signal from the noise.”

Patients enrolled in the trial will undergo dilated eye examinations at intervals depending on which arm enrolls them, and both arms enrolling patients with neovascular AMD will treat those patients with ranibizumab, including retreatment as needed. Blood will be drawn to screen for the antibodies under investigation, and visual acuity and retinal thickness as seen on OCT will be measured for secondary endpoints of the study. Understandably, patients with autoimmune disorders or conditions being treated with immunosuppressant drugs, such as prednisone and infliximab, are excluded. RP