Ranibizumab and Bevacizumab for Wet AMD: The CATT Comes Out of the Bag

Published - Written by Jennifer Zeis

The results of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT), a head-to-head comparison of ranibizumab and bevacizumab for the treatment of the neovascular (or wet) form of age-related macular degeneration (AMD), have been eagerly anticipated.

In October 2006, researchers reported in NEJM that intravitreal administration of ranibizumab for two years prevented vision loss and improved mean visual acuity in patients with AMD with minimally classic or occult choroidal neovascularization. Age-related macular degeneration is the leading cause of blindness in the U.S.

This 2006 study, the MARINA trial, was a successful test of a recombinant monoclonal antibody directed against the vascular endothelial growth factor A (VEGF-A) protein. When VEGF is inhibited, the growth of neovascular blood vessels slows; and leakage from these newly-formed vessels, which greatly diminishes vision, also slows or stops. There have been two VEGF inhibitors that have been used in this fashion: bevacizumab (FDA-approved in 2004 as a treatment of metastatic colon cancer) and ranibizumab (the subject of the MARINA trial and FDA-approved in June 2006 for treatment of neovascular AMD.

Until ranibizumab’s FDA approval in 2006, clinicians used bevacizumab off-label for wet AMD because it targets VEGF and is therefore thought to work in a similar way to ranibizumab. And, naturally, many asked for a head-to-head comparison of the two drugs, including Dr. Edwin Stone, the NEJM editorialist on the MARINA trial.

The launch of this study, the CATT, was bumpy. The study did not have a pharmaceutical company sponsor or partner that would contribute the medications or offset their cost. One government grant was needed to cover the cost of bevacizumab, and a revision to the Medicare Clinical Trial policy was necessary to support the cost of ranibizumab. Later, “an exceptional circumstance” exception was invoked under the NIH Grants Policy Statement to cover ranibizumab’s 20% Medicare copayment – per patient, around $5,000 for one year – for those patients who did not have supplemental prescription drug coverage, according to CATT investigators in a 2010 NEJM Perspective article.

By December 2009, 1,208 patients were enrolled at 44 U.S. clinical centers. To be eligible for the trial, patients had to be over 50, had to have previously untreated active choroidal neovascularization due to AMD in the eye being studied, and had to have at least a modest impairment of visual acuity. Investigators also confirmed that patients had neovascularization, fluid, or hemorrhage under the fovea.

The study had four arms, because the researchers compared the effects of bevacizumab and ranibizumab on two dosage schedules: each drug was administered either monthly or as-needed. In a paper published this week in NEJM, Dr. Daniel Martin and colleagues report that the two drugs had essentially equivalent effects on visual acuity at all time points throughout the first year of follow-up for 1,185 patients treated at 43 clinical centers. They also found that for both drugs “excellent” results for visual acuity could be achieved with as-needed administration as well with the traditional monthly regimens.

Dr. Philip Rosenfeld, author of the NEJM editorial on the CATT study, writes that these results support the use of either drug for neovascular AMD. He adds, “An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required.”

When dosing-regimen groups were combined, the proportions of patients with serious systemic adverse events were 24.1% for bevacizumab and 19.0% for ranibizumab.  Rosenfeld writes, “Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy.

The results from the second year of CATT and from five other large, ongoing, multicenter comparative clinical trials in Europe should help to clarify whether these adverse events are related to intravitreal anti-VEGF therapy.”

NEJM Deputy Editor Elizabeth Phimister said the “statistically robust” findings are important to clinical practice. “This study is so entrenched in day-to-day treatment of people with this disease,” she said.

 

Will the results of CATT change how you treat your patients?